Prodrugs of gamma-hydroxybutyric acid, compositions and uses thereof

ABSTRACT

The present disclosure discloses prodrugs of gamma-hydroxybutyric acid as well as compositions and uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/CN2016/099763, filed on Sep. 22, 2016, which claims benefit ofInternational Application No. PCT/CN2015/090326, filed on Sep. 23, 2015and further claims benefit of Chinese Patent Application No.201610782104.1, filed on Aug. 13, 2016. The entire disclosure of each ofthe aforesaid applications is incorporated by reference in the presentapplication.

FIELD OF THE INVENTION

The present disclosure generally relates to prodrugs ofgamma-hydroxybutyric acid (GHB), as well as compositions and usesthereof.

BACKGROUND OF THE INVENTION

Narcolepsy is a chronic neurological disorder characterized by excessivedaytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogichallucinations, and disturbed nocturnal sleep. EDS is usually presentand appears first. Cataplexy occurs in approximately 70% of patientswith narcolepsy while the other symptoms feature less frequently and invarious combinations. The prevalence of narcolepsy in the United Statesand Europe ranges from 20 to 67 per 100,000.

GHB is a naturally-occurring central nervous system (CNS) transmitter.The GHB sodium salt also called sodium oxybate, currently being marketedby Jazz Pharmaceuticals plc as Xyrem, is the first and only drugapproved by the U.S. Food and Drug Administration (FDA) to treatcataplexy associated with narcolepsy. Sodium oxybate has been shown tobe highly efficacious with a ˜70% reduction of the total number ofcataplexy episodes. In Europe, sodium oxybate is used medicinally forvarious purposes including narcolepsy, alcohol dependence, and opiatedependence. In November 2005, the FDA approved an expanded indicationfor sodium oxybate as a treatment for excessive daytime sleepiness(EDS). In addition, sodium oxybate has also been conducted in theclinical trial in the U.S. for fibromyalgia syndrome, a pain offibromyalgia that is notoriously difficult to treat. Sodium oxybate alsohas potential to treat other CNS disorders such as insomnia,hallucinogenic dreams and sleep paralysis.

Despite its efficacious effect and advantageous position in treating EDSand cataplexy associated with narcolepsy, sodium oxybate displays asub-optimal pharmacokinetics profile that makes it difficult to provideoptimal therapeutic benefits. The deficiencies of sodium oxybateinclude: 1) variable oral bioavailability and unpredictable drug plasmaconcentrations resulting from its erratic absorption in patients; 2)short plasma half-life (t_(1/2)<1 hr); 3) significant food effect (highfat meal may significantly delay and decrease absorption of sodiumoxybate); 4) high bolus oral dosing caused unpleasant GI disturbance; 5)poor patient compliance and inconvenient drug administration (due to thetwice per night dosage regimen); 6) risk of hypernatremia (due to intakeof large amount of sodium salt form compounds). Consequently, thesedeficiencies prevent sodium oxybate from providing the maximumtherapeutic benefit that it can possibly achieve. Therefore, thereremains a continuing need for compounds derived from GHB to overcomesome or all of the above described deficiencies.

SUMMARY OF THE INVENTION

The present disclosure provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein the variables are defined below.

The present disclosure further provides a pharmaceutical compositioncomprising one or more compounds of the present disclosure.

The present disclosure also provides use of one or more compounds in themanufacture of a medicament for treating a disease, wherein the diseaseis narcolepsy, excessive daytime sleepiness, cataplexy,neurodegenerative disease, sleep disturbance syndrome, fibromyalgia,chronic fatigue, schizophrenia, binge eating disorder, Parkinsondisease, tardive dyskinesia, or Alzheimer's disease.

The present disclosure further provides a method of treating a disease,comprising administering to a subject an effective amount of one or morecompounds of the present disclosure, wherein the disease is narcolepsy,excessive daytime sleepiness, cataplexy, neurodegenerative disease,sleep disturbance syndrome, fibromyalgia, chronic fatigue,schizophrenia, Binge eating disorder, Parkinson disease, tardivedyskinesia, or Alzheimer's disease.

The present disclosure also provides a compound of the presentdisclosure for use in any of the methods described herein.

DETAILED DESCRIPTION OF THE INVENTION

Compound

In one aspect, the present disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

B is

—(O)R¹, —R²(OCO)R³, substituted or unsubstituted C₅₋₁₀ aryl, C₁₋₁₂alkyl, C₅₋₁₂ aralkyl, C₂₋₁₂ alkenyl, C₆₋₁₂ aralkenyl, C₂₋₁₂ alkynyl,C₃₋₈ cycloalkyl, 3-10 membered heterocyclic alkyl, or 5-10 memberedheterocyclic aryl, wherein the one or more substituents are selectedfrom the group consisting of C₁₋₁₂ alkyl, amino, substituted amino,amino protecting group, —R⁴—S—R⁵, halogen, hydroxyl, cyano, mono-, di-or tri-halo-C₁₋₆ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₁₋₁₂ alkoxy,C₅₋₁₀ aryl, C₅₋₁₀ alkylaryl, C₃₋₈ cycloalkyl, C₁₋₁₂ alkylsulfonyl, 3-8membered heterocyclic alkyl, 3-10 membered heterocyclic aryl, C₅₋₁₀aryloxyl, C₅₋₁₀ arylcarbonyl, C₁₋₆ alkylcarbonyloxyl or C₁₋₄alkyloxycarbonyl;

wherein

R¹ and R³ are independently C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₅₋₁₂ aralkyl,C₆₋₁₂ aralkenyl, C₂₋₁₂ alkynyl, C₅₋₁₀ aryl, C₃₋₈ cycloalkyl, 3-10membered heterocyclic alkyl, 5-10 membered heterocyclic aryl, or

any of which can be optionally mono- or independently multi-substitutedby —R⁴—S—R⁵, halogen, hydroxyl, cyano, amino, substituted amino, C₁₋₁₂alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₅₋₁₀ aryl, C₁₋₁₂ alkoxy, C₃₋₈cycloalkyl, 3-8 membered heterocyclic alkyl, or 3-10 memberedheterocyclic aryl, C₁₋₄ alkylsulfonyl, C₅₋₁₀ aryloxyl, C₅₋₁₀arylcarbonyl, C₁₋₄ alkyloxycarbonyl, or C₁₋₁₂ alkylcarbonylamino;

R² is C₁₋₆ alkylene or C₁₋₆ alkyleneoxyl, any of which is optionallyfurther substituted with C₁₋₆ alkyl;

R⁴ is a bond, C₁₋₆ alkylene, C₅₋₁₀ arylene, or C₅₋₁₂ arylenealkylene,any of which is optionally further substituted with C₁₋₃ alkyl, and R⁵is hydrogen or C₁₋₁₂ alkyl,

-   -   R_(g) is hydrogen, C₁₋₆ alkyl, phenyl, or phenylmethyl, any of        which is optionally mono- or independently multi-substituted by        halogen, hydroxyl, methylthio, C₁₋₄ alkyl, or C₅₋₈ aryl; and        R_(h) and R_(f) are independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxylcarbonyl, C₃₋₆ cycloalkoxylcarbonyl,        or an amino protecting group;    -   or    -   R_(f) and R_(g) together with C, O, N or S atom form a 4-8        membered heterocyclic alkyl or

-   -    any of which is optionally mono- or independently        multi-substituted by halogen, hydroxyl or C₁₋₄ alkyl, and R_(h)        is hydrogen, C₁₋₆ alkyl or an amino protecting group.

In some embodiments, B is C₁₋₈ alkyl substituted with C₂₋₆ alkyl, arylor amino group and B is not linear alkyl. In some embodiments, B is C₂₋₆alkenyl substituted with C₁₋₆ alkyl, aryl or amino group. In someembodiments, B is substituted or unsubstituted C₃₋₈ cycloalkyl, whereinthe substituent is selected from the group consisting of halogen,hydroxyl and C₁₋₆ alkyl. In some embodiments, B is substituted orunsubstituted 3-8 membered heterocyclic alkyl, wherein the substituentis selected from the group consisting of halogen, hydroxyl and C₁₋₆alkyl. In some embodiments, B is substituted or unsubstituted 5-8membered heterocyclic aryl, wherein the substituent is selected from thegroup consisting of halogen, hydroxyl and C₁₋₆ alkyl.

In some embodiments, B is —CHR¹³R¹⁴, wherein R¹³ and R¹⁴ areindependently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₅₋₁₀ aryl and amino group, wherein R¹³ and R¹⁴ cannot be methylat the same time. In some embodiments, R¹³ and R¹⁴ can be cyclized toform a C₃₋₈ cycloalkyl. In some embodiments, R¹³ and R¹⁴ together with aO, N or S atom form a 3-8 membered heterocyclic alkyl.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (IA):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R_(g) is hydrogen, C₁₋₆ alkyl, phenyl, or phenylmethyl, any of which isoptionally mono- or independently multi-substituted by halogen,hydroxyl, methylthio, C₁₋₄ alkyl, or C₅₋₈ aryl; and R_(h) and R_(f) areindependently hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxylcarbonyl, C₃₋₆ cycloalkoxylcarbonyl or an amino protecting group.

In some embodiments, R_(g) is hydrogen or C₁₋₃ alkyl. In someembodiments, at least one of R_(h) and R_(f) is hydrogen or C₁₋₃ alkyl.In some embodiments, both R_(h) and R_(f) are hydrogen or C₁₋₃ alkyl. Insome embodiments, R_(h) is hydrogen or C₁₋₃ alkyl and R_(f) is —COR⁵,and R⁵ is C₁₋₃ alkyl, C₁₋₃ alkoxyl, or C₅₋₆ cycloalkyloxyl. In someembodiments, when R_(f) or R_(h) is an amino protecting group, R_(g) isnot isopropyl or benzyl.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (IA):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R_(f) and R_(g) together with C, O, or N atom form a 4-6 memberedheterocyclic alkyl or

any of which is optionally mono- or independently multi-substituted byhalogen, hydroxyl, C₁₋₄ alkyl or an amino protecting group;

R_(h) is hydrogen, C₁₋₃ alkyl or an amino protecting group.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (IA-1):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R_(h) is hydrogen, C₁₋₃ alkyl or an amino protecting group.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (IA-2):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R_(i) is hydrogen, C₁₋₄ alkyl or an amino protecting group.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (IB):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R¹ is C₁₋₈ alkyl, C₅₋₈ aryl, C₅₋₁₂ aralkyl, 3-10 membered heterocyclicalkyl or

any of which is optionally mono- or independently multi-substituted byhalogen, cyano, hydroxyl, C₁₋₁₂ alkyl or C₁₋₄ alkoxy.

In some embodiments, R¹ is

and wherein R_(1a) and R_(1b) are independently hydrogen, C₁₋₁₂ alkyl,C₁₋₄ alkoxy or halogen. In some embodiments, R¹ is

and R_(1c) is hydrogen, C₁₋₁₂ alkyl or halogen.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (IC):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R_(a), R_(b), R_(c), R_(d) and R_(e) are independently hydrogen,halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, cyano, C₁₋₁₂ alkylsulfonyl, C₁₋₆alkylcarbonyloxyl, C₁₋₄ alkyloxycarbonyl, mono-, di- or tri-halo-C₁₋₆alkyl, C₅₋₁₀ aryloxyl or C₅₋₁₀ arylcarbonyl; and

when R_(a), R_(b), R_(c), R_(d) and R_(e) are all hydrogen, at least oneof R_(a), R_(b), R_(c), R_(d) and R_(e) is not protium.

In some embodiments, R_(b), R_(c), R_(d) are all hydrogen, and R_(e) andR_(a) are independently hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ alkoxy,cyano, C₁₋₃ alkylsulfonyl, C₁₋₃ alkylcarbonyloxyl, C₁₋₃alkyloxycarbonyl, or mono-, di- or tri-halo-C₁₋₃ alkyl. In someembodiments, one of R_(e) and R_(a) is hydrogen. In some embodiments,not all of R_(a), R_(b), R_(c), R_(d) and R_(e) are hydrogen at the sametime.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (ID):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R² is —(CR⁶R⁷)_(m)—, wherein m=1-6 and R⁶ and R⁷ are independentlyhydrogen or C₁₋₃ alkyl;

R³ is C₁₋₁₂ alkyl, C₅₋₈ aryl, 3-8 membered heterocyclic alkyl, or 5-8membered heterocyclic aryl, which are each optionally mono- orindependently multi-substituted by halogen, unsubstituted or substitutedamino, C₁₋₆ alkyl or C₁₋₆ alkoxy; wherein when the amino is substitutedit can be optionally mono- or independently multi-substituted by C₁₋₆alkyl, or C₁₋₆ alkylcarbonyl.

In some embodiment, R² is —CH₂—. In some embodiment, R³ is methyl,ethyl, phenyl, which are each optionally mono- or independentlymulti-substituted by methoxyl, methyl or ethyl.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (ID-1):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R_(3a), R_(3b), R_(3c), R_(3d) and R_(3e) are independently hydrogen,halogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (ID-2):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R⁹ and R¹⁰ are independently hydrogen, C₁₋₆ alkyl or C₁₋₆ alkylcarbonyl;and R⁸ is hydrogen or C₁₋₆ alkyl.

The present disclosure also provides a compound having the chemicalstructure shown in Formula (IE):

or a pharmaceutically acceptable salt, ester, hydrate, or solvatethereof, wherein,

R¹¹ is C₁₋₈ alkyl or C₅₋₈ aryl, any of which is optionally mono- orindependently multi-substituted by halogen, hydroxyl, C₁₋₆ alkyl or C₁₋₄alkoxy;

R¹² is hydrogen or C₁₋₆ alkyl.

In some embodiments, the molecular weight of each of the compoundsdisclosed herein is no more than 450 Da. In some embodiments, themolecular weight of each of the compounds disclosed herein is 150-450Da, 150-300 Da, or 200-300 Da.

In some embodiments, the compound is selected from:

Various features of the present disclosure that are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

As used herein, the term “substituted”, when refers to a chemical group,means the chemical group has one or more hydrogen atoms that is/areremoved and replaced by substituents. As used herein, the term“substituent” has the ordinary meaning known in the art and refers to achemical moiety that is covalently attached to, or if appropriate fusedto, a parent group. As used herein, the term “optionally substituted”means that the chemical group may have no substituents (i.e.unsubstituted) or may have one or more substituents (i.e. substituted).It is to be understood that substitution at a given atom is limited byvalency.

As used herein, the term “C_(n-m)” indicates a range of the carbon atomsnumbers, wherein n and m are integers and the range of the carbon atomsnumbers includes the endpoints (i.e. n and m) and each integer point inbetween. For examples, C₁₋₆ indicates a range of one to six carbonatoms, including one carbon atom, two carbon atoms, three carbon atoms,four carbon atoms, five carbon atoms and six carbon atoms.

As used herein, the term “alkyl”, whether as part of another term orused independently, refers to a saturated hydrocarbon group that may bestraight-chain or branched-chain. The term “C_(n-m) alkyl” refers to analkyl having n to m carbon atoms. In some embodiments, the alkyl groupcontains 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbonatoms. Examples of alkyl group include, but are not limited to, chemicalgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl,3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

As used herein, the term “alkenyl”, whether as part of another term orused independently, refers to an unsaturated hydrocarbon group that maybe straight-chain or branched-chain having at least one carbon-carbondouble bond. The term “C_(n-m) alkenyl” refers to an alkenyl having n tom carbon atoms. In some embodiments, the alkenyl group contains 2 to 12,2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. In someembodiments, the alkenyl group contains 1 to 6, 1 to 5, 1 to 4, 1 to 3,1 to 2, or 1 carbon-carbon double bond. Examples of alkenyl groupsinclude, but are not limited to, chemical groups such as ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, the term “alkynyl”, whether as part of another term orused independently, refers to an unsaturated hydrocarbon group that maybe straight-chain or branched-chain having at least one carbon-carbontriple bonds. The term “C_(n-m) alkynyl” refers to an alkynyl having nto m carbon atoms. In some embodiments, the alkynyl group contains 2 to12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 carbon atoms. Insome embodiments, the alkynyl group contains 1 to 6, 1 to 5, 1 to 4, 1to 3, 1 to 2, or 1 carbon-carbon triple bond. Examples of alkynyl groupsinclude, but are not limited to, chemical groups such as ethynyl,propyn-1-yl, propyn-2-yl, and the like.

As used herein, the term “alkylene”, whether as part of another term orused independently, refers to a bivalent saturated hydrocarbon moietieswhich is linear, or branched, and which connects two other parts of amolecule. The term “C_(n-m) alkylene” refers to an alkylene having n tom carbon atoms. In some embodiments, the alkylene group contains 1 to12, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 carbon atoms.Examples of alkylene groups include, but are not limited to, chemicalgroups such as methylene, ethylene, 1-methyl-methylene, propylidene,butylidene and the like.

As used herein, the term “aryl” or “aromatic”, whether as part ofanother term or used independently, refers to a mono- or polycycliccarbocyclic ring system radicals with alternating double and singlebonds between carbon atoms forming the rings. In some embodiments, thearyl ring systems have 5 to 10, 5 to 8, or 5 to 6 carbon atoms in one ormore rings. In some embodiment, the aryl ring system have 2 or morerings fused together. Examples of aryl groups include, but are notlimited to, chemical groups such as phenyl, naphthyl,tetrahydronaphthyl, indanyl, idenyl and the like.

As used herein, the term “arylene”, whether as part of another term orused independently, refers to a divalent aryl ring or ring system whichconnects two other parts of a molecule, i.e. the two parts are bonded tothe ring in two distinct ring positions. When the aryl ring of thearylene is a monocyclic ring system, the two parts are bonded to thesame ring in two distinct ring positions. When the aryl ring of thearylene is a polycyclic ring system, the two parts can be bonded to thesame ring or different rings in two distinct ring positions. Arylene maybe substituted or unsubstituted. Unsubstituted arylene has nosubstituents other than the two parts of the molecule it connects.Substituted arylene has substituents in addition to the two parts of themolecule it connects.

As used herein, the term “aralkyl”, whether as part of another term orused independently, refers to a group of formula -alkyl-aryl. The term“C_(n-m) aralkyl” refers to aralkyl with a total carbon number between nto m. In some embodiments, the alkyl moiety has 1 to 6, 1 to 4, 1 to 3,or 1 to 2 carbon atoms. In some embodiments, the aralkyl group has 5-12,5-10, 5-8, or 6-7 carbon atoms. Examples of aralkyl groups include, butare not limited to, various alkyl benzenes and alkyl naphthalenes.

As used herein, the term “arylenealkylene”, whether as part of anotherterm or used independently, refers to a group of formula-alkylene-arylene, wherein the arylene and alkylene groups are aspreviously described, wherein the term “C_(n-m) arylenealkylene” refersto an arylenealkylene group with a total carbon number between n to m.In some embodiments, the alkylene portion of the arylenealkylene moietyhas 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. In some embodiments,the arylene portion of the arylenealkylene moiety has 6 to 12, 6 to 11,6 to 10, 6 to 9, or 6 to 8 ring forming carbon atoms. In someembodiments, the arylenealkylene moiety has 7-12, 7-10, 7-9, or 7-8carbon atoms.

As used herein, the term “aralkenyl”, whether as part of another term orused independently, refers to a group of formula -alkenyl-aryl, whereinthe term “C_(n-m) aralkenyl” refers to an aralkenyl group with a totalcarbon number between n to m. In some embodiments, the alkenyl moietycontains 2 to 12, 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, or 2 to 3carbon atoms. In some embodiments, the aralkenyl group has 6-18, 6-12,6-10, 6-8, or 6-7 carbon atoms. Examples of aralkenyl groups include,but are not limited to, chemical groups such as styryl, 3-(benzyl)prop-2-enyl, and 6-napthylhex-2-enyl.

As used herein, the term “cycloalkyl”, whether as part of another termor used independently, refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. In some embodiments, the cycloalkyl is saturatedcycloalkyl. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8 ring-formingcarbons (C₃-8). Examples of cycloalkyl groups include, but are notlimited to, chemical groups such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl,cyclohexadienyl, cycloheptatrienyl, and the like. In some embodiments, acycloalkyl used herein may be fused (i.e., having a bond in common with)with one or more aromatic rings, for example, benzo or thienylderivatives of cyclopentane, cyclohexane, and the like. In someembodiments, a cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring.

As used herein, the term “cycloalkylene”, whether as part of anotherterm or used independently, refers to a bivalent saturated or partiallysaturated non-aromatic cyclic hydrocarbons group, and which connects twoother parts of a molecule. The term “C_(n-m) cycloalkylene” refers to acycloalkylene having n to m carbon atoms. In some embodiments, thecycloalkylene group contains 3 to 12, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3to 5, or 3 to 4 carbon atoms. Examples of cycloalkylene groups include,but are not limited to, chemical groups such as cyclopropylidene,cyclobutalidene and the like.

As used herein, the term “alkoxy”, whether as part of another term orused independently, refers to a group of formula —O-alkyl. The term“C_(n-m) alkoxy” means that the alkyl moiety of the alkoxy group has nto m carbon atoms. In some embodiments, the alkyl moiety has 1 to 6, 1to 4, or 1 to 3 carbon atoms. Examples of alkoxy groups include, but arenot limited to, chemical groups such as methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), t-butoxy, and the like.

As used herein, the term “aryloxyl” refers to a group of formula—O-aryl, wherein the aryl group is as previously described. “C_(n-m)aryloxyl” means that the aryl moiety of the aryloxyl group has n to mcarbon atoms. In some embodiments, the aryl moiety has 5 to 10, 5 to 8,or 5 to 6 carbon atoms.

As used herein, the term “alkylamino”, whether as part of another termor used independently, refers to a group of formula —NH-alkyl. The term“C_(n-m) alkylamino” means that the alkyl moiety of the alkylamino grouphas n to m carbon atoms. In some embodiments, the alkyl moiety has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “arylcarbonyl”, whether as part of another termor used independently, refers to a group of formula —C(═O)-aryl, whereinthe aryl group is as previously described. “C_(n-m) arylcarbonyl” meansthat the aryl moiety of the arylcarbonyl group has n to m carbon atoms.In some embodiments, the aryl moiety has 5 to 10, 5 to 8, or 5 to 6carbon atoms.

As used herein, the term “alkylcarbonyl”, whether as part of anotherterm or used independently, refers to a group of formula —C(═O)-alkyl.The term “C_(n-m) alkylcarbonyl” means that the alkyl moiety of thealkylcarbonyl group has n to m carbon atoms. In some embodiments, thealkyl moiety has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.

As used herein, the term “alkoxycarbonyl”, whether as part of anotherterm or used independently, refers to a group of formula —C(═O)—O-alkyl.The term “C_(n-m) alkoxycarbonyl” means that the alkyl moiety of thealkoxycarbonyl group has n to m carbon atoms. In some embodiments, thealkyl moiety has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.

As used herein, the term “cycloalkoxylcarbonyl”, whether as part ofanother term or used independently, refers to a group of formula—C(═O)—O-cycloalkyl, wherein the cycloalkyl group is as previouslydescribed. The term “C_(n-m) cycloalkyloxylcarbonyl” means that thecycloalkyl moiety of the cycloalkoxylcarbonyl group has n to m carbonatoms. In some embodiments, the cycloalkyl moiety has 3 to 8, 3 to 6, 3to 5 or 3 to 4 carbon atoms.

As used herein, the term “alkylcarbonyloxyl”, whether as part of anotherterm or used independently, refers to a group of formula —O—C(═O)-alkyl.The term “C_(n-m) alkylcarbonyloxyl” means that the alkyl moiety of thealkylcarbonyloxyl group has n to m carbon atoms. In some embodiments,the alkyl moiety has 1 to 6, 1 to 4, 1 to 3 or 1 to 2 carbon atoms.

As used herein, the term “n membered”, wherein n is an integer typicallyemployed in combination with a ring system to describe the number ofring-forming atoms in the ring system. For example, piperidinyl is anexample of a 6 membered heterocycloalkyl ring, pyrazolyl is an exampleof a 5 membered heteroaryl ring, pyridyl is an example of a 6 memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10 membered cycloalkyl group.

As used herein, the term “heterocyclic aryl” refers to aryl groupwherein at least one ring atom in the aromatic ring is a heteroatom, andthe remainder of the ring atoms being carbon atoms. The term “n-mmembered heterocyclic aryl” refers to heterocyclic aryl having n to mring-forming members. Example heteroatoms include, but are not limitedto, oxygen, sulfur, nitrogen, phosphorus, and the like. In someembodiments, heterocyclic aryl can have 5 to 10, 5 to 8, or 5 to 6ring-forming members. In some embodiments, heterocyclic aryl is 5membered or 6 membered heterocyclic aryl. Examples of heterocyclic arylinclude, but are not limited to, furanyl, thienyl, pyridyl, pyrrolyl,N-lower alkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl,imidazolyl, indolyl and the like.

A 5 membered heterocyclic aryl is a heterocyclic aryl with a ring havingfive ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms canbe independently selected from N, O, P, and S. Exemplary 5 memberedheterocyclic aryl are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A 6 membered heterocyclic aryl is a heterocyclic aryl with a ring havingsix ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms can beindependently selected from N, O, P, and S. Exemplary 6 memberedheterocyclic aryl are pyridyl, pyrazinyl, pyrimidinyl, triazinyl andpyridazinyl.

As used herein, the term “heterocyclic alkyl” refers to cycloalkyl groupwherein at least one ring atom in the ring systems is a heteroatom, andthe remainder of the ring atoms being carbon atoms. The term “n-mmembered heterocyclic alkyl” refers to heterocyclic alkyl having n to mring-forming members. In addition, the ring may also have one or moredouble bonds, but not have a completely conjugated system. In someembodiments, the heterocyclic alkyl is saturated heterocyclic alkyl.Examples of heteroatoms include, but are not limited to, oxygen, sulfur,nitrogen, phosphorus, and the like. In some embodiments, heterocyclicalkyl has 3 to 8, 3 to 6, or 4 to 6 ring-forming carbons. Examples ofheterocyclic alkyl include, but are not limited to, azetidine,aziridine, pyrrolidyl, piperidyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperazinyl, and the like.

As used herein the terms “halo” and “halogen” refer to an atom selectedfrom fluorine, chlorine, bromine and iodine.

As used herein, “mono-, di- or tri-halo-C_(n-m) alkyl” refers to analkyl group that is substituted by one, two or three halo, wherein thealkyl group has n to m carbon atoms and the halo as substituent may besame or different. Examples of mono-, di- or tri-halo-C_(n-m) alkylinclude without limitation, trichloromethyl, chloromethyl,bischloromethyl, chlorobromomethyl.

As used herein the terms “cyano” refer to a group of formula —CN.

As used herein, the term “hydroxyl” refers to a group of formula —OH.

As used herein, the term “methylthio” refers to a group of formula—S—CH₃.

As used herein, the term “alkylsulfonyl” refers to a group of formula-sulfonyl-alkyl. The term “C_(n-m) alkylsulfonyl” refers toalkylsulfonyl wherein the alkyl moiety has n to m carbon atoms. In someembodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.Examples of alkylsulfonyl groups include without limitation,methanesulfonyl, ethanesulfonyl, tert-butanesulfonyl, and the like.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “substituted amino” refers to an amino that ismono- or independently substituted by one or more substituents. Examplesof substituents include, but are not limited to, halogen, hydroxyl, C₁₋₄alkyl, C₅₋₈ aryl, C₁₋₆ alkoxyl, C₃₋₈ cycloalkyl, 3-8 memberedheterocyclic alkyl, or 3-8 membered heterocyclic aryl, C₁₋₄alkylsulfonyl, C₅₋₁₀ aryloxyl, C₅₋₁₀ arylcarbonyl or C₁₋₆alkyloxycarbonyl, amino protecting group, and the like.

As used herein, the term “amino protecting group” refers to asubstituent that protects an amino functionality against undesirablereactions during synthetic procedures. Examples of amino protectinggroups include, but are not limited to, carbamate-protecting groups,such as 2-trimethyl-silylethoxycarbonyl (Teoc),1-methyl-1-(4-bi-phenyl-yl)-ethoxy-carbonyl (Bpoc), t-butoxycarbonyl(Boc), allyloxycarbonyl (Alloc), 9-fluorenyl-methyloxycarbonyl (Fmoc),and benzyl-oxycarbonyl (Cbz); amide-protecting groups, such as formyl,acetyl, trihaloacetyl, benzoyl, and nitrophenylacetyl;sulfona-mide-protecting groups, such as 2-nitrobenzenesulfonyl; andimine- and cyclic imide-protecting groups, such as phthalimido anddithiasuccinoyl.

As used herein, the term “compound” is meant to include allstereoisomers (eg. enantiomers and diastereomers), geometric iosomers,tautomers, and isotopes of the structures depicted. Compounds hereinidentified by name or structure as one particular tautomeric form areintended to include other tautomeric forms unless otherwise specified.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent disclosure that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, carbon-carbon double bonds, and the like can also be present inthe compounds described herein, and all such stable isomers arecontemplated in the present disclosure. Cis and trans geometric isomersof the compounds of the present disclosure are described and may beisolated as a mixture of isomers or as separated isomeric forms.

In some embodiments, the compounds described herein have the(R)-configuration. In some embodiments, the compounds described hereinhave the (S)-configuration.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a chiral resolving acid, which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asβ-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the present disclosure also include tautomeric forms.Tautomeric forms result from the swapping of a single bond with anadjacent double bond together with the concomitant migration of aproton. Tautomeric forms include prototropic tautomers which areisomeric protonation states having the same empirical formula and totalcharge. Example prototropic tautomers include ketone-enol pairs,amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, andannular forms where a proton can occupy two or more positions of aheterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the present disclosure can also include all isotopes ofatoms occurring in the intermediates or final compounds. Isotopesinclude those atoms having the same atomic number but different massnumbers. For example, isotopes of hydrogen include protium, deuteriumand tritium. In some embodiments, the isotope of hydrogen is protium anddeuterium. In some embodiments, the hydrogens on the aromatic ring ofthe compounds include at least one deuterium. In some embodiments, thehydrogens on the aromatic ring of the compounds are all deuteriums.

In some embodiments, the compounds of the present disclosure can convertto GHB after oral administration. In some embodiments, the compounds ofthe present disclosure can enter into human circulatory system through abiological process after oral administration. In some embodiment, thecompounds of the present disclosure convert to GHB in liver. In someembodiment, the compounds of the present disclosure convert to GHB inblood. In some embodiment, the GHB releasing efficiency of the compoundswithin 1 hour after contacting blood or liver is no less than 90%, 80%,70%, 60%, 50%, 40%, 30%, 20%, or 10%. In some embodiment, the GHBreleasing efficiency of the compounds within 2 hours after contactingblood or liver is no less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, or20%.

In some embodiments, the compounds of the present disclosure have higheroral bioavailability than the oral bioavailability of GHB sodium salt.In some embodiments, the oral bioavailability of the compounds of thepresent disclosure is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2,2.5, 3, or 4 times higher than the oral bioavailability of GHB sodiumsalt. In some embodiments, the compounds of the present disclosure havehigher colonic absorption than the colonic absorption of GHB. In someembodiments, the colonic absorption of the compounds of the presentdisclosure is 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5. 3, 4,5, 6, 8, or 10 times higher than the colonic absorption of GHB. In someembodiment, the oral bioavailability of the compounds of the presentdisclosure is no less than 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

Not to be limited by the theory, the nature of compounds of the presentdisclosure enables the compounds to be formulated to a stable solidformulation, especially the sustained or controlled-release formulation.For example, some compounds of the present disclosure can be formulatedinto a drug with controlled absorption in GI tract. In some embodiment,the oral absorption of the compounds in the colon is no less than 40%,50%, 60%, 70%, 80%, 90% or more of the total oral absorption.

Synthesis Method

Compounds of the present disclosure, including salts, esters, hydrates,or solvates thereof, can be prepared using any known organic synthesistechniques and can be synthesized according to any of numerous possiblesynthetic routes.

The reactions for preparing compounds of the present disclosure can becarried out in suitable solvents, which can be readily selected by oneskilled in the art of organic synthesis. Suitable solvents can besubstantially non-reactive with the starting materials (reactants), theintermediates, or products at the temperatures at which the reactionsare carried out, e.g., temperatures that can range from the solvent'sfreezing temperature to the solvent's boiling temperature. A givenreaction can be carried out in one solvent or a mixture of more than onesolvent. Depending on the particular reaction step, suitable solventsfor a particular reaction step can be selected by a skilled artisan.

Preparation of compounds of the present disclosure can involve theprotection and deprotection of various chemical groups. The need forprotection and deprotection, and the selection of appropriate protectinggroups, can be readily determined by one skilled in the art. Thechemistry of protecting groups can be found, for example, in T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., Wiley & Sons, Inc., New York (1999), which is incorporated hereinby reference in its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography. Exemplary syntheticschemes are listed below, the abbreviations for the reactants or for thechemical groups of the reactants included in the synthetic schemes aredefined in the Examples.

For example, compounds of Formula I can be formed as shown in Scheme 1.

Alternatively, compounds of Formula I can be formed as shown in Scheme2.

For example, compounds of Formula IA can be formed as shown in Scheme 3(X in the scheme refers to any substituent group).

A representative compound of Formula IA can be formed as shown in Scheme4.

A representative compound of Formula IA can be formed as shown in Scheme5.

Alternatively, the compounds of Formula IA can be formed as shown inScheme 6 (wherein X in the scheme refers to any substituent group).

A representative compound of Formula IA can be formed as shown in Scheme7.

A representative compound of Formula IA can be formed as shown in Scheme8.

A representative compound of Formula IA-2 can be formed as shown inScheme 9.

For example, compounds of Formula IB can be formed as shown in Scheme10.

A representative compound of Formula IB can be formed as shown in Scheme11.

A representative compound of Formula IB can be formed as shown in Scheme12.

For example, compounds of Formula ID can be formed as shown in Scheme13.

A representative compound of Formula ID-2 can be formed as shown inScheme 14.

A representative compound of Formula ID-2 can be formed as shown inScheme 15.

A representative compound of Formula ID-2 can be formed as shown inScheme 16.

For example, compounds of Formula IE can be formed as shown in Scheme17.

Pharmaceutical Composition

The present disclosure provides pharmaceutical composition comprisingone or more compounds of the present disclosure, and a pharmaceuticallyacceptable carrier.

These pharmaceutical compositions can be prepared in a manner well knownin the pharmaceutical art. In some embodiments, the compounds of thepresent disclosure may be admixed with pharmaceutically acceptablecarrier for the preparation of pharmaceutical composition.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. In some embodiments,compounds, materials, compositions, and/or dosage forms that arepharmaceutically acceptable refer to those approved by a regulatoryagency (such as U.S. Food and Drug Administration, China Food and DrugAdministration or European Medicines Agency) or listed in generallyrecognized pharmacopoeia (such as U.S. Pharmacopoeia, ChinaPharmacopoeia or European Pharmacopoeia) for use in animals, and moreparticularly in humans.

As used herein, the term “pharmaceutically acceptable carrier” refers toany and all solvents, excipients, coatings, antibacterial and antifungalagents, flavoring agents, isotonic and absorption delaying agents, andthe like that are pharmaceutically acceptable and can facilitate storageand administration of the compounds of the present disclosure to asubject. Pharmaceutically acceptable carrier that can be employed inpresent disclosure includes those generally known in the art, such asthose described in “Remington Pharmaceutical Sciences” Mack Pub. Co.,New Jersey (1991), which is incorporated herein by reference.

Examples of pharmaceutically acceptable carriers include, but are notlimited to, solvents, liposomes, polymeric excipients and the like.

In certain embodiments, the pharmaceutically acceptable carrier is asolvent that can dissolve or disperse the compounds of the presentdisclosure. Illustrative examples of solvent include, withoutlimitation, buffer saline, normal saline, phosphate buffer, citratebuffer, acetate buffer, bicarbonate buffer, sucrose solution,polysorbate solution, oil, ester, and alcohol.

In certain embodiments, the pharmaceutically acceptable carriers areliposomes, and the compounds of the present disclosure can beencapsulated within the aqueous portion or lipid portion of theliposomes. Illustrative examples of liposomes include, withoutlimitation, liposomes based on 3 [N-(N′,N′-dimethylaminoethane)carbamoyl] cholesterol (DC-Chlo), liposomes based onN-(2,3-dioleoyloxy)propyl-N,N,N-trimethylammonium chloride (DOTMA), andliposomes based on 1,2-dioleoyloxy-3-trimethylammonium propane (DOTAP).

In certain embodiments, the pharmaceutically acceptable carriers arepolymeric excipients such as, without limitation, microspheres,microcapsules, polymeric micelles and dendrimers. The compounds of thepresent disclosure may be encapsulated, adhered to, or coated on thepolymer-based components by methods known in the art.

The form of pharmaceutical compositions depends on a number of criteria,including, but not limited to, route of administration, extent ofdisease, or dose to be administered. The pharmaceutical compositions canbe formulated for oral, nasal, rectal, percutaneous, intravenous, orintramuscular administration. In accordance to the desired route ofadministration, the pharmaceutical compositions can be formulated in theform of tablets, pills, powders, lozenges, sachets, cachets,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium) or ointments.

For oral administration, powders, granules, pills, tablets, caplets,capsules, and gelcaps are acceptable as solid dosage forms. These can beprepared, for example, by mixing one or more compounds of the presentdisclosure with at least one carrier such as sucrose, lactose, cellulosesugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates,chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins,collagens, casein, albumin, synthetic or semi-synthetic polymers orglycerides, methyl cellulose, hydroxypropylmethyl-cellulose, and/orpolyvinylpyrrolidone. In some embodiments, solid dosage forms for oraladministration can further comprise other carrier ingredients to aid inmanufacture or administration with lubricants such as magnesiumstearate, or preservatives such as paraben or sorbic acid, oranti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agents, or chelating agents such as EDTA, binders,thickeners, flavoring agents or perfuming agents. In certainembodiments, solid dosage forms for oral administration may additionallycomprise dyestuffs or pigments for identification. Tablets and pills maybe further treated with suitable coating materials known in the art,such as moisture protective, enteric, or sustained release coatings.

For oral administration, emulsions, syrups, elixirs, suspensions,slurries and solutions are acceptable as liquid dosage forms. These canbe prepared, for example, by mixing one or more compounds of the presentdisclosure with sterile inactive solvent, such as but not limited to,water, alcohol, oil and a combination thereof. In some embodiments, theinactive diluent used in the liquid dosage form for oral administrationcomprise oil, such as but not limited to, peanut oil, sesame oil,cottonseed oil, corn oil and olive oil. In some embodiments, theinactive diluent used in the liquid dosage form for oral administrationcomprise esters of fatty acids, such as but not limited to, ethyloleate, isopropyl myristate, fatty acid glycerides and acetylated fattyacid glycerides. In some embodiments, the inactive diluent used in theliquid dosage form for oral administration comprise alcohols, such asbut not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol,glycerol and propylene glycol. In some embodiment, liquid dosage formsfor oral administration can further comprise surfactants, suspendingagents, emulsifying agents, stabilizers, flavoring agents, chelatingagents, preservatives, antioxidants, solubilizers (such as propyleneglycol, glycerin, or sorbitol), dyes, or thickeners. In someembodiments, the liquid dosage form for oral administration can furthercomprise pH adjusting agent, such as but not limited to, sodiumhydroxide, hydrochloric acid, or malic acid.

The pharmaceutical composition of the present disclosure can beformulated so as to provide quick, sustained or delayed release of theactive ingredient after administration to the patient by employingprocedures known in the art. In some embodiments, the composition isformulated in a sustained released form. As used herein, the term“sustained released form” refers to release of the active agent from thepharmaceutical composition so that it becomes available forbio-absorption in the subject, primarily in the gastrointestinal tractof the subject, over a prolonged period of time (extended release), orat a certain location (controlled release). In some embodiments, theprolonged period of time can be about 1 hour to 24 hours, 2 hours to 12hours, 3 hours to 8 hours, 4 hours to 6 hours, 1 to 2 days or more. Incertain embodiments, the prolonged period of time is at least about 4hours, at least about 8 hours, at least about 12 hours, or at leastabout 24 hours.

In some embodiments, the sustained release form of pharmaceuticalcompositions are tablets or pills, and the tablets or pills are coatedor otherwise formulated to provide a dosage form affording the advantageof prolonged action. Factors affecting drug release are well known tothe skilled artisan and have been described in the art (Bamba et al.,Int. J. Pharm., 1979, 2, 307), which is incorporated herein by referencein its entirety. For example, release rate of the active agent can notonly be controlled by dissolution of the active agent ingastrointestinal fluid and subsequent diffusion out of the tablet orpills independent of pH, but can also be influenced by physicalprocesses of disintegration and erosion of the tablet. In someembodiments, polymeric materials as described in “Medical Applicationsof Controlled Release,” Langer and Wise (eds.), CRC Pres., Boca Raton,Fla. (1974); “Controlled Drug Bioavailability,” Drug Product Design andPerformance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger andPeppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61; see also Levyet al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351;Howard et al., 1989, J. Neurosurg. 71:105 can be used for sustainedrelease. The above references are incorporated herein by reference inits entirety.

In some embodiments, polymeric materials are used for oral sustainedrelease delivery. Examples of the polymeric materials include sodiumcarboxymethylcellulose, hydroxypropyl cellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose. Other celluloseethers have been described in Alderman, Int. J. Pharm. Tech. & Prod.Mfr., 1984, 5(3) 1-9, which is incorporated herein by reference in itsentirety. In some embodiments, enteric-coated preparations can be usedfor oral sustained release administration. Examples of the coatingmaterials include polymers with a pH-dependent solubility (i.e.,pH-controlled release), polymers with a slow pH-dependent rate ofswelling, dissolution or erosion (i.e., time-controlled release),polymers that are degraded by enzymes (i.e., enzyme-controlled release)and polymers that form firm layers that are destroyed by an increase inpressure (i.e., pressure-controlled release). In some embodiments,osmotic delivery systems are used for oral sustained releaseadministration as described in Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708, which is incorporated herein by reference in itsentirety. In a preferred ambodiment, OROS™ osmotic devices are used fororal sustained release delivery devices as described in Theeuwes et al.,U.S. Pat. No. 3,845,770; Theeuwes et al., U.S. Pat. No. 3,916,899, whichare incorporated herein by reference in its entirety. In someembodiments, a controlled-release system can be placed in proximity ofthe target of the compounds and/or composition of the presentdisclosure, thus requiring only a fraction of the systemic dose, see,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984), which is incorporated herein by reference inits entirety. Other controlled-release systems as described in Langer,1990, Science 249:1527-1533 may also be used, which is incorporatedherein by reference in its entirety.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 0.5 to about 30 g, about 1 to about 20 g, about 2to about 20 g, about 3 to about 20 g, about 4 to about 20 g, about 5 toabout 20 g, about 6 to about 20 g, about 7 to about 20 g, about 8 toabout 20 g, about 9 to about 20 g, about 10 to about 20 g, about 11 toabout 20 g, about 12 to about 20 g, about 13 to about 20 g, about 14 toabout 20 g, about 15 to about 20 g, about 16 to about 20 g, about 17 toabout 20 g, about 18 to about 20 g, 2 to about 18 g, about 2 to about 16g, about 2 to about 14 g, about 2 to about 12 g, about 2 to about 10 g,about 2 to about 9 g, about 2 to about 8 g, about 2 to about 6 g of theactive ingredient. The term “unit dosage forms” refers to physicallydiscrete units suitable as unitary dosages for human subjects and othermammals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier.

Method for Treatment

The present disclosure provides, a method of treating a disease,comprising administering to a subject an effective amount of one or morecompounds of the present disclosure.

In some embodiments, the disease is narcolepsy, excessive daytimesleepiness, cataplexy, neurodegenerative disease, sleep disturbancesyndrome, fibromyalgia, chronic fatigue, schizophenia, binge eatingdisorder, Parkinson disease, tardive dyskinesia, or Alzheimer's disease.In some embodiments, the disease is excessive daytime sleepiness orcataplexy associated with narcolepsy.

Administration may be via oral, nasal, intravenous, subcutaneous,sublingual, or intramuscular administration.

The frequency of administration of the compounds will vary dependingupon what is being administered, the amount of the therapeutic agent,the purpose of the administration, the state of the patient, the mannerof administration, and the like. Determination of frequency ofadministration is well within the capability of those skilled in theart. In some embodiments, the administration is conducted no more thantwo time per day, no more than one time per day, no more than two timesper three days, no more than one time per two days, no more than onetime per three days, no more than one time per five days, no more thanone time per one week, or no more than one time per two weeks.

As used herein, the term “effective amount” means an amount of thetherapeutic agent that is effective to provide a desired outcome.Determination of a therapeutically effective amount is well within thecapability of those skilled in the art. Generally, a therapeuticallyeffective amount can vary with the subject's history, age, condition,sex, as well as the severity and type of the medical condition in thesubject, and administration of other agents that inhibit pathologicalprocesses in neurodegenerative disorders. In some embodiments, theeffective amount of the therapeutic agent is from about 0.5 to about 30g, about 1 to about 15 g, about 2 to about 15 g, about 3 to about 10 g,about 4 to about 10 g.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers to delaying onset of the disease or disorder;ameliorating at least one of the clinical symptoms relating to thedisease or disorder; or both.

Pharmaceutical Use

The present disclosure also provides use of one or more compounds of thepresent disclosure in the manufacture of a medicament for treating adisease. In some embodiments, the disease is narcolepsy, excessivedaytime sleepiness, cataplexy, neurodegenerative disease, sleepdisturbance syndrome, fibromyalgia, chronic fatigue, schizophenia, bingeeating disorder, Parkinson disease, tardive dyskinesia, or Alzheimer'sdisease. In some embodiments, the disease is excessive daytimesleepiness or cataplexy associated with narcolepsy.

The present disclosure also provides the compounds of the presentdisclosure for treating a disease. In some embodiments, the disease isnarcolepsy, excessive daytime sleepiness, cataplexy, neurodegenerativedisease, sleep disturbance syndrome, fibromyalgia, chronic fatigue,schizophenia, binge eating disorder, Parkinson disease, tardivedyskinesia, or Alzheimer's disease. In some embodiments, the disease isexcessive daytime sleepiness or cataplexy associated with narcolepsy.

EXAMPLES

The following examples are presented to illustrate the presentdisclosure. They are not intended to be limiting in any manner.

Example 1: Preparation and Characterization of Exemplary Compounds

Compounds encompassed in the present disclosure may be prepared viadifferent schemes. Detailed preparation processes of 90 exemplarycompounds via various schemes are described below and thecharacterization results are listed for each compound as well.

Unless stated otherwise, all reagents were purchased from commercialsuppliers without further purification. Solvent drying by standardmethods was employed when necessary. The plates used for thin-layerchromatography (TLC) were E. Merck silica gel 60F254 (0.24 nm thickness)precoated on aluminum plates, and then visualized under UV light (365 nmand 254 nm) or through staining with a 5% of dodecamolybdophosphoricacid in ethanol and subsequent heating. Column chromatography wasperformed using silica gel (200-400 mesh) from commercial suppliers. ¹HNMR spectra were recorded on an Agilent 400-MR NMR spectrometer (400.00MHz for 1H) at room temperature. Solvent signal was used as referencefor ¹H NMR (CDCl₃, 7.26 ppm; CD₃OD, 3.31 ppm; d₆-DMSO, 2.50 ppm; D₂O,4.79 ppm). The following abbreviations were used to explain themultiplicities: s=singlet, d=doublet, t=triplet, q=quartet, br.s.=broadsinglet, dd=double doublet, td=triple doublet, dt=double triplet,dq=double quartet, m=multiplet. Other abbreviations used in theexperimental details are as follows: Ar=aryl, Boc=tert-butyloxycarbonyl, Bn=Benzyl, δ=chemical shift in parts per million downfieldfrom tetramethylsilane, DCC=dicyclohexylcarbodiimide,DCM=dichloromethane, DIPEA=diisopropylethylamine,DMAP=4-(dimethylamino)pyridine, DMF=N,N′-dimethylformamide, EA=ethylacetate, Et=ethyl,HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate, Hex.=hexanes, Hz=hertz, J=coupling constant(in NMR), Me=methyl, min=minute (s), NMR=nuclear magnetic resonance,Ph=phenyl, ppm=parts per million, iPr=isopropyl, TBAF=tetrabutylammoniumfluoride, tert=tertiary, TFA=trifluoroacetic acid, THF=tetrahydrofuran,TLC=thin-layer chromatography.

Example 1-1 Intermediate Compound 1′: 4-hydroxybutyl 2-methylbenzoate

A solution of 2-methylbenzoyl chloride (770 mg, 5 mmol) in DCM (2 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (8 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was then washedwith saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated.The residue was purified by a silica gel flash column withHex/EA=10:1-3:1 to yield the titled compound (470 mg, 45%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.91 (d,J=8.0 Hz, 1H), 7.40 (t, J=7.4 Hz, 1H), 7.26-7.22 (m, 2H), 4.34 (t, J=6.8Hz, 2H), 3.73 (t, J=6.4 Hz, 2H), 2.60 (s, 3H), 1.90-1.83 (m, 2H),1.77-1.70 (m, 2H).

Compound 1: 4-(2-methylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-methylbenzoate (400 mg, 1.92 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), then dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by a silica gel flash column with Hex/EA=3:1 to yield thetitled compound (380 mg, 89%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.91 (d, J=8.0 Hz, 1H), 7.40 (t,J=7.8 Hz, 1H), 7.28-7.22 (m, 2H), 4.36 (t, J=6.2 Hz, 2H), 2.61 (s, 3H),2.55 (t, J=7.4 Hz, 2H), 2.15-2.08 (m, 2H).

Example 1-2 Intermediate Compound 2′: 4-hydroxybutyl 3-methylbenzoate

A solution of 3-methylbenzoyl chloride (616 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was then washedwith saturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated.The residue was purified by a silica gel flash column withHex/EA=10:1-3:1 to yield the titled compound (410 mg, 49%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.83-7.81(m, 2H), 7.35-7.28 (m, 2H), 4.33 (t, J=6.6 Hz, 2H), 3.70 (t, J=6.4 Hz,2H), 2.38 (s, 3H), 2.07 (s, 1H), 1.89-1.82 (m, 2H), 1.75-1.68 (m, 2H).

Compound 2: 4-(3-methylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-methylbenzoate (350 mg, 1.68 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=3:1 to yield thetitled compound (333 mg, 89%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.83-7.81 (m, 2H), 7.36-7.28 (m, 2H), 4.36 (t,J=6.2 Hz, 2H), 2.53 (t, J=7.2 Hz, 2H), 2.38 (s, 3H), 2.14-2.07 (m, 2H).

Example 1-3 Intermediate Compound 3′: 4-hydroxybutyl 4-methylbenzoate

A solution of 4-methylbenzoyl chloride (616 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-3:1to yield the titled compound (470 mg, 56%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.91 (d, J=8.4 Hz, 2H), 7.20(d, J=8.4 Hz, 2H), 4.32 (t, J=6.6 Hz, 2H), 3.69 (t, J=6.6 Hz, 2H), 2.38(s, 3H), 2.19 (br. s., 1H), 1.87-1.80 (m, 2H), 1.74-1.67 (m, 2H).

Compound 3: 4-(4-methylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-methylbenzoate (400 mg, 1.92 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=3:1 to yield thetitled compound (364 mg, 85%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.91 (d, J=8.0 Hz, 2H), 7.23 (d,J=8.0 Hz, 2H), 4.36 (t, J=6.2 Hz, 2H), 2.54 (t, J=7.4 Hz, 2H), 2.40 (s,3H), 2.14-2.08 (m, 2H).

Example 1-4 Intermediate Compound 4′: 4-hydroxybutyl 4-fluorobenzoate

A solution of 4-fluorobenzoyl chloride (632 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-3:1to yield the titled compound (540 mg, 64%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=8.07-8.04 (m, 2H), 7.11 (t,J=8.6 Hz, 2H), 4.36 (t, J=6.4 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H), 1.90-1.83(m, 2H), 1.76-1.69 (m, 2H), 1.41 (br. s., 1H).

Compound 4: 4-(4-fluorobenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-fluorobenzoate (500 mg, 2.36 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (356 mg, 67%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=8.06-8.03 (m, 2H), 7.11 (t, J=8.6Hz, 2H), 4.38 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H), 2.15-2.07 (m,2H).

Example 1-5 Intermediate Compound 5′: 4-hydroxybutyl2,4,6-trimethylbenzoate

A solution of 2,4,6-trimethylbenzoyl chloride (728 mg, 4 mmol) in DCM (5mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. was added a solution of 2,4,6-trimethylbenzoyl chloride (728mg, 4 mmol) in DCM (5 mL) dropwise during 10 min. The reaction wasallowed to warm up gradually and stirred at 0-25° C. for over 1 h. Afterthat, the reaction mixture was diluted with H₂O (5 mL) and stirred for 5min. The aqueous phase was separated and extracted with DCM (5 mL). Thecombined organic phase was washed with saturated brine (5 mL), driedover anhydrous Na₂SO₄ and evaporated. The residue was purified by asilica gel flash column with Hex/EA=10:1-3:1 to yield the titledcompound (600 mg, 64%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=6.85 (s, 2H), 4.34 (t, J=6.6 Hz, 2H), 3.69 (t, J=6.6Hz, 2H), 2.29 (s, 6H), 2.28 (s, 3H), 1.88-1.80 (m, 2H), 1.73-1.66 (m,2H), 1.49 (br. s., 1H).

Compound 5: 4-(2,4,6-trimethylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2,4,6-trimethylbenzoate (500 mg, 2.12 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1-3:1 to yield thetitled compound (450 mg, 85%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=6.85 (s, 2H), 4.36 (t, J=6.4 Hz, 2H), 2.51 (t,J=7.2 Hz, 2H), 2.29 (s, 6H), 2.28 (s, 3H), 2.12-2.05 (m, 2H).

Example 1-6 Intermediate Compound 6′: 4-hydroxybutyl 2-methoxybenzoate

A solution of 2-methoxybenzoyl chloride (680 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-5:1to yield the titled compound (370 mg, 41%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.79 (dd, J=1.6, 7.6 Hz, 1H),7.49-7.45 (m, 1H), 7.00-6.97 (m, 2H), 4.35 (t, J=6.2 Hz, 2H), 3.90 (s,3H), 3.77-3.68 (m, 2H), 1.91-1.83 (m, 2H), 1.77-1.69 (m, 2H), 1.56 (br.s., 1H).

Compound 6: 4-(2-methoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-methoxybenzoate (300 mg, 1.34 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-3:1 to yield thetitled compound (244 mg, 76%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.78 (dd, J=1.8, 7.8 Hz, 1H),7.49-7.45 (m, 1H), 7.00-6.96 (m, 2H), 4.36 (t, J=6.0 Hz, 2H), 3.90 (s,3H), 2.57 (t, J=7.4 Hz, 2H), 2.13-2.07 (m, 2H).

Example 1-7 Intermediate Compound 7′: 4-hydroxybutyl 3-methoxybenzoate

A solution of 3-methoxybenzoyl chloride (680 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-3:1to yield the titled compound (420 mg, 47%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.63 (d, J=7.6 Hz, 1H), 7.56(s, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.10 (dd, J=2.4, 8.0 Hz, 1H), 4.36 (t,J=6.4 Hz, 2H), 3.85 (s, 3H), 3.73 (t, J=6.2 Hz, 2H), 1.91-1.84 (m, 2H),1.76-1.69 (m, 2H).

Compound 7: 4-(3-methoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-methoxybenzoate (350 mg, 1.56 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=8:1-3:1 to yield thetitled compound (287 mg, 77%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.63 (d, J=8.0 Hz, 1H), 7.55 (s,1H), 7.35 (t, J=7.8 Hz, 1H), 7.10 (dd, J=2.4, 8.0 Hz, 1H), 4.39 (t,J=6.4 Hz, 2H), 3.86 (s, 3H), 2.54 (t, J=7.2 Hz, 2H), 2.16-2.08 (m, 2H).

Example 1-8 Intermediate Compound 8′: 4-hydroxybutyl 4-methoxybenzoate

A solution of 4-methoxybenzoyl chloride (680 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-5:1to yield the titled compound (500 mg, 56%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.99 (d, J=9.2 Hz, 2H), 6.91(d, J=8.8 Hz, 2H), 4.33 (t, J=6.6 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 2H),1.89-1.82 (m, 2H), 1.76-1.69 (m, 2H), 1.44 (br. s., 1H).

Compound 8: 4-(4-methoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-methoxybenzoate (400 mg, 1.79 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-3:1 to yield thetitled compound (370 mg, 87%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.99 (d, J=9.2 Hz, 2H), 6.92 (d, J=8.8 Hz,2H), 4.35 (t, J=6.2 Hz, 2H), 3.86 (s, 3H), 2.54 (t, J=7.2 Hz, 2H),2.13-2.08 (m, 2H).

Example 1-9 Intermediate Compound 9′: 4-hydroxybutyl 2-chlorobenzoate

A solution of 2-chlorobenzoyl chloride (2 g, 11.43 mmol) in DCM (10 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (3085 mg, 34.28 mmol) and Et₃N (2308 mg, 22.85 mmol) inDCM (50 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 16 h. After that, the reaction mixture wasdiluted with H₂O (30 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (10 mL). The combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=8:1 to yield thetitled compound (1.8 g, 69%) as colorless oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.81 (dd, J=1.4, 7.8 Hz, 1H), 7.45-7.38 (m,2H), 7.34-7.28 (m, 1H), 4.38 (t, J=6.4 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H),1.91-1.84 (m, 2H), 1.77-1.70 (m, 2H).

Compound 9: 4-(2-chlorobenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-chlorobenzoate (1.6 g, 7.02 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (20 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with brine (3 mL×2),dried over Na₂SO₄ and concentrated. The residue was purified by a silicagel flash column with Hex/EA=3:1 to yield the titled compound (1 g, 59%)as crystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=7.82 (dd, J=1.2, 8.0 Hz, 1H), 7.49-7.38 (m, 2H), 7.34-7.29 (m, 1H),4.41 (t, J=6.2 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 2.16-2.09 (m, 2H).

Example 1-10 Intermediate Compound 10′: 4-hydroxybutyl 3-chlorobenzoate

A solution of 3-chlorobenzoyl chloride (696 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-5:1to yield the titled compound (550 mg, 60%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=8.00 (s, 1H), 7.92 (d, J=7.6Hz, 1H), 7.52 (dd, J=0.8, 8.4 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 4.36 (t,J=6.4 Hz, 2H), 3.73 (dd, J=6.2, 10.6 Hz, 2H), 1.91-1.84 (m, 2H),1.76-1.69 (m, 3H).

Compound 10: 4-(3-chlorobenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-chlorobenzoate (500 mg, 2.19 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-3:1 to yield thetitled compound (420 mg, 79%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=8.00 (s, 1H), 7.92 (d, J=7.6 Hz, 1H),7.55-7.52 (m, 1H), 7.39 (t, J=7.8 Hz, 1H), 4.39 (t, J=6.2 Hz, 2H), 2.55(t, J=7.2 Hz, 2H), 2.16-2.09 (m, 2H).

Example 1-11 Intermediate Compound 11′: 4-hydroxybutyl 4-chlorobenzoate

A solution of 4-chlorobenzoyl chloride (2 g, 11.43 mmol) in DCM (10 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (3085 mg, 34.28 mmol) and Et₃N (2308 mg, 22.85 mmol) inDCM (50 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 1 h. After that, the reaction mixture wasdiluted with H₂O (30 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (10 mL). The combined organic phase waswashed with brine (20 mL), dried over Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=7:1 to yield thetitled compound (1.6 g, 62%) as crystalline solids. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.97 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz,2H), 4.36 (t, J=6.6 Hz, 2H), 3.73 (t, J=6.4 Hz, 2H), 1.90-1.84 (m, 2H),1.75-1.69 (m, 2H).

Compound 11: 4-(4-chlorobenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-chlorobenzoate (1.5 g, 6.58 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 16 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (20 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with brine (3 mL×2),dried over Na₂SO₄ and concentrated. The residue was purified by a silicagel flash column with Hex/EA=3:1 to afford the title compound (600 mg,38%) as crystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃as solvent to characterize the titled compound, results are as follows:δ=7.96 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 4.39 (t, J=6.2 Hz,2H), 2.54 (t, J=7.2 Hz, 2H), 2.15-2.07 (m, 2H).

Example 1-12 Intermediate Compound 12′: 4-hydroxybutyl 3-cyanobenzoate

A solution of 3-cyanobenzoyl chloride (660 mg, 4 mmol) in DCM (5 mL) wasadded dropwise during 10 min to a stirred solution of butane-1,4-diol(450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0° C. Thereaction was allowed to warm up gradually and stirred at 0-25° C. forover 1 h. After that, the reaction mixture was diluted with H₂O (5 mL)and stirred for 5 min. The aqueous phase was separated and extractedwith DCM (5 mL). The combined organic phase was washed with saturatedbrine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=10:1-5:1 to yieldthe titled compound (450 mg, 51%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=8.31 (s, 1H), 8.26 (d, J=8.0 Hz,1H), 7.83 (d, J=7.6 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 4.39 (t, J=6.4 Hz,2H), 3.73 (t, J=6.4 Hz, 2H), 1.92-1.85 (m, 2H), 1.76-1.69 (m, 2H).

Compound 12: 4-(3-cyanobenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-cyanobenzoate (400 mg, 1.83 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-3:1 to yield thetitled compound (330 mg, 77%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.85 (d,J=7.6 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 2.56 (t,J=7.2 Hz, 2H), 2.18-2.11 (m, 2H).

Example 1-13 Intermediate Compound 13′: 4-hydroxybutyl4-tert-butylbenzoate

A solution of 4-tert-butylbenzoyl chloride (784 mg, 4 mmol) in DCM (5mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-5:1to yield the titled compound (530 mg, 53%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.97 (d, J=8.0 Hz, 2H), 7.45(d, J=8.8 Hz, 2H), 4.35 (t, J=6.4 Hz, 2H), 3.73 (t, J=6.2 Hz, 2H),1.91-1.83 (m, 2H), 1.76-1.71 (m, 2H), 1.34 (s, 9H).

Compound 13: 4-(4-tert-butylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-tert-butylbenzoate (450 mg, 1.8 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-3:1 to yield thetitled compound (370 mg, 79%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.96 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.8 Hz,2H), 4.37 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.4 Hz, 2H), 2.15-2.06 (m, 2H),1.34 (s, 9H).

Example 1-14 Intermediate Compound 14′: 4-hydroxybutyl3-(trifluoromethyl)benzoate

A solution of 3-(trifluoromethyl)benzoyl chloride (832 mg, 4 mmol) inDCM (5 mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. over 12 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-5:1to yield the titled compound (670 mg, 64%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=8.29 (s, 1H), 8.23 (d, J=8.0Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 4.40 (t, J=6.4Hz, 2H), 3.74 (t, J=6.6 Hz, 2H), 1.93-1.86 (m, 2H), 1.77-1.70 (m, 2H),1.42 (br. s., 1H).

Compound 14: 4-(3-(trifluoromethyl)benzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-(trifluoromethyl)benzoate (600 mg, 2.29 mmol) andCelite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column withHex/EA=10:1-3:1 to yield the titled compound (400 mg, 63%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=8.29 (s,1H), 8.22 (d, J=8.0 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.59 (t, J=7.6 Hz,1H), 4.43 (t, J=6.4 Hz, 2H), 2.55 (t, J=7.4 Hz, 2H), 2.18-2.12 (m, 2H).

Example 1-15 Intermediate Compound 15′: 4-hydroxybutyl3,4,5-trimethoxybenzoate

A solution of 3,4,5-trimethoxybenzoyl chloride (920 mg, 4 mmol) in DCM(5 mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. over 12 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-4:1to yield the titled compound (700 mg, 62%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.29 (s, 2H), 4.35 (t, J=6.6Hz, 2H), 3.90 (s, 9H), 3.77-3.69 (m, 2H), 1.92-1.84 (m, 2H), 1.75-1.68(m, 2H), 1.48 (br. s., 1H).

Compound 15: 4-(3,4,5-trimethoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3,4,5-trimethoxybenzoate (600 mg, 2.11 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=8:1-3:1 to yield thetitled compound (440 mg, 70%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.28 (s, 2H), 4.37 (t, J=6.4 Hz,2H), 3.90 (s, 9H), 2.52 (t, J=7.2 Hz, 2H), 2.15-2.08 (m, 2H).

Example 1-16 Intermediate Compound 16′: 4-hydroxybutyl 4-ethylbenzoate

A solution of 4-ethylbenzoyl chloride (500 mg, 2.98 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (534 mg, 5.93 mmol) and Et₃N (599 mg, 5.93 mmol) in DCM(10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. for over 1 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=10:1-6:1 to yield the titled compound (450 mg, 68%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.97 (s,1H), 7.94 (s, 1H), 7.27 (s, 1H), 7.25 (s, 1H), 4.35 (t, J=6.4 Hz, 2H),3.73 (t, J=6.2 Hz, 2H), 2.70 (q, J=7.6 Hz, 2H), 1.90-1.83 (m, 2H),1.77-1.70 (m, 2H), 1.34 (br. s., 1H), 1.25 (t, J=7.6 Hz, 3H).

Compound 16: 4-(4-ethylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-ethylbenzoate (450 mg, 2.03 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (270 mg, 56%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.96 (s, 1H), 7.94 (s, 1H), 7.27 (s, 1H), 7.25(s, 1H), 4.37 (t, J=6.2 Hz, 2H), 2.70 (q, J=7.6 Hz, 2H), 2.55 (t, J=7.4Hz, 2H), 2.15-2.09 (m, 2H), 1.25 (t, J=7.6 Hz, 3H).

Example 1-17 Intermediate Compound 17′: 4-hydroxybutyl2,3-dimethylbenzoate

A solution of 2,3-dimethylbenzoyl chloride (500 mg, 2.97 mmol) in DCM (5mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (534 mg, 5.93 mmol) and Et₃N (599 mg, 5.93 mmol) in DCM(10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 3 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=7:1 to yield the titled compound (390 mg, 59%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.61 (d,J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 4.34 (t,J=6.6 Hz, 2H), 3.73 (t, J=6.0 Hz, 2H), 2.45 (s, 3H), 2.32 (s, 3H),1.90-1.83 (m, 2H), 1.78-1.69 (m, 2H), 1.36 (br. s., 1H).

Compound 17: 4-(2,3-dimethylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2,3-dimethylbenzoate (350 mg, 1.58 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-6:1 to yield thetitled compound (230 mg, 62%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.61 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.2 Hz,1H), 7.13 (t, J=7.6 Hz, 1H), 4.35 (t, J=6.2 Hz, 2H), 2.54 (t, J=7.2 Hz,2H), 2.45 (s, 3H), 2.32 (s, 3H), 2.15-2.08 (m, 2H).

Example 1-18 Intermediate Compound 18′: 4-hydroxybutyl3,5-dimethoxybenzoate

A solution of 3,5-dimethoxybenzoyl chloride (500 mg, 2.49 mmol) in DCM(5 mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (10mL) at 0° C. The reaction was allowed to warm up gradually and stirredat 0-25° C. over 3 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=7:1 toyield the titled compound (430 mg, 68%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.18 (d, J=2.4 Hz, 2H), 6.65 (t,J=2.0 Hz, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.83 (s, 6H), 3.73 (t, J=6.2 Hz,2H), 1.90-1.83 (m, 2H), 1.76-1.69 (m, 2H).

Compound 18: 4-(3,5-dimethoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3,5-dimethoxybenzoate (400 mg, 1.57 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (200 mg, 47%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.16 (d, J=2.4 Hz, 2H), 6.64 (t, J=2.0 Hz,1H), 4.37 (t, J=6.2 Hz, 2H), 3.82 (s, 6H), 2.52 (t, J=7.2 Hz, 2H),2.14-2.07 (m, 2H).

Example 1-19 Intermediate Compound 19′: 4-hydroxybutyl3,5-dimethylbenzoate

A solution of 3,5-dimethylbenzoyl chloride (500 mg, 2.96 mmol) in DCM (5mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (534 mg, 5.93 mmol) and Et₃N (599 mg, 5.93 mmol) in DCM(10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 16 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=7:1 to yield the titled compound (400 mg, 61%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.65 (s,2H), 7.19 (s, 1H), 4.35 (t, J=6.4 Hz, 2H), 3.73 (s, 2H), 2.36 (s, 6H),1.90-1.83 (m, 2H), 1.77-1.70 (m, 2H).

Compound 19: 4-(3,5-dimethylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3,5-dimethylbenzoate (400 mg, 1.8 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (300 mg, 70%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.64 (s, 2H), 7.19 (s, 1H), 4.36 (t, J=6.0 Hz,2H), 2.55 (t, J=7.4 Hz, 2H), 2.36 (s, 6H), 2.15-2.08 (m, 2H).

Example 1-20 Intermediate Compound 20′: 4-hydroxybutyl cinnamate

A solution of cinnamoyl chloride (664 mg, 4 mmol) in DCM (5 mL) wasadded dropwise during 10 min to a stirred solution of butane-1,4-diol(450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL) at 0° C. Thereaction was allowed to warm up gradually and stirred at 0-25° C. forover 1 h. After that, the reaction mixture was diluted with H₂O (5 mL)and stirred for 5 min. The aqueous phase was separated and extractedwith DCM (5 mL). The combined organic phase was washed with saturatedbrine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=10:1-3:1 to yieldthe titled compound (455 mg, 52%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.69 (d, J=16.0 Hz, 1H), 7.54-7.52(m, 2H), 7.39 (t, J=3.2 Hz, 3H), 6.44 (d, J=16.0 Hz, 1H), 4.25 (t, J=6.4Hz, 2H), 3.72 (t, J=6.2 Hz, 2H), 1.85-1.78 (m, 2H), 1.73-1.66 (m, 2H),1.44 (br. s., 1H).

Compound 20: (E)-4-(cinnamoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl cinnamate (400 mg, 1.81 mmol) and Celite® (diatomaceousearth, 2 g) in acetone (5 mL) at 0° C. The reaction proceeded at 0° C.for over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of iPrOH, diluted withEA (10 mL) and then filtered. The filtered cake was washed with EA (5mL) and the combined filtrate was washed with saturated brine (2 mL×2),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby a silica gel flash column with Hex/EA=3:1 to yield the titledcompound (370 mg, 87%) as colorless oil. ¹H NMR was performed at 400 MHzwith CDCl₃ as solvent to characterize the titled compound, results areas follows: δ=7.68 (d, J=16.0 Hz, 1H), 7.54-7.52 (m, 2H), 7.40-7.38 (m,3H), 6.43 (d, J=16.0 Hz, 1H), 4.26 (t, J=6.2 Hz, 2H), 2.48 (t, J=7.2 Hz,2H), 2.07-2.01 (m, 2H).

Example 1-21 Intermediate Compound 21′: 4-hydroxybutyl3-phenylpropanoate

A solution of 3-phenylpropanoyl chloride (672 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-3:1to yield the titled compound (370 mg, 42%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.31-7.27 (m, 2H), 7.21-7.19(m, 3H), 4.10 (t, J=6.6 Hz, 2H), 3.65 (t, J=6.4 Hz, 2H), 2.95 (t, J=7.8Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.73-1.66 (m, 2H), 1.60-1.54 (m, 2H),1.33 (br. s., 1H).

Compound 21: 4-(3-phenylpropanoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-phenylpropanoate (300 mg, 1.35 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=3:1 to yield thetitled compound (277 mg, 87%) as colorless oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.31-7.27 (m, 2H), 7.22-7.19 (m, 3H), 4.12 (t,J=6.2 Hz, 2H), 2.95 (t, J=7.8 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 2.37 (t,J=7.4 Hz, 2H), 1.96-1.90 (m, 2H).

Example 1-22 Intermediate Compound 22′: 4-hydroxybutyl pivalate

A solution of pivaloyl chloride (1.2 g, 10 mmol) was added dropwiseduring 10 min to a stirred solution of butane-1,4-diol (2.7 g, 30 mmol)and Et₃N (2.02 g, 20 mmol) in DCM (30 mL) at 0° C. The reaction wasallowed to warm up gradually and stirred at 0˜25° C. over 1 h. Afterthat, the reaction mixture was diluted with H₂O (10 mL) and stirred for5 min. The aqueous phase was separated and extracted with DCM (15 mL).The combined organic phase was washed with brine (15 mL), dried overNa₂SO₄ and evaporated. The residue was purified by a silica gel flashcolumn with Hex/EA=20:1-5:1 to yield the titled compound (1.5 g, 86%) asa colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solventto characterize the titled compound, results are as follows: δ=4.09 (t,J=6.0 Hz, 2H), 3.68 (t, J=6.4 Hz, 2H), 1.74-1.70 (m, 2H), 1.65-1.61 (m,2H), 1.19 (s, 9H).

Compound 22: 4-(pivaloyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl pivalate (1.0 g, 5.75 mmol) and Celite® (diatomaceousearth, 2 g) in acetone (20 mL) at 0° C. The reaction proceeded at 0° C.over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of iPrOH, diluted withEA (20 mL) and then filtered. The filtered cake was washed with EA (10mL) and the combined filtrate was washed with brine (5 mL×2), dried overNa₂SO₄ and concentrated. The residue was purified by a silica gel flashcolumn with Hex/EA=5:1 to yield the titled compound (700 mg, 65%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=4.11 (t,J=6.4 Hz, 2H), 2.46 (t, J=7.4 Hz, 2H), 2.02-1.95 (m, 2H), 1.19 (s, 9H).

Example 1-23 Intermediate Compound 23′: 4-hydroxybutyl 2-ethylbutanoate

A solution of 2-ethylbutanoyl chloride (500 mg, 3.7 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (669 mg, 7.43 mmol) and Et₃N (750 mg, 7.43 mmol) in DCM(10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 3 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=6:1 to yield the titled compound (450 mg, 65%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=4.13 (t,J=6.4 Hz, 2H), 3.73-3.64 (m, 2H), 2.23-2.16 (m, 1H), 1.77-1.70 (m, 2H),1.68-1.58 (m, 4H), 1.55-1.46 (m, 2H), 0.89 (t, J=7.4 Hz, 6H).

Compound 23: 4-(2-ethylbutanoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-ethylbutanoate (450 mg, 2.39 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (300 mg, 62%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.14 (t, J=6.2 Hz, 2H), 2.46 (t, J=7.6 Hz,2H), 2.24-2.17 (m, 1H), 2.02-1.95 (m, 2H), 1.66-1.46 (m, 4H), 0.89 (t,J=7.4 Hz, 6H).

Example 1-24 Intermediate Compound 24′: 4-hydroxybutyl2-propylpentanoate

A solution of 2-propylpentanoyl chloride (1 g, 6.13 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (1107 mg, 12.3 mmol) and Et₃N (1242 mg, 12.3 mmol) inDCM (10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 16 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=5:1 to yield the titled compound (700 mg, 53%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=4.11 (t,J=6.6 Hz, 2H), 3.69 (q, J=5.8 Hz, 2H), 2.39-2.32 (m, 1H), 1.77-1.69 (m,2H), 1.68-1.60 (m, 3H), 1.58-1.53 (m, 1H), 1.45-1.36 (m, 3H), 1.33-1.24(m, 4H), 0.89 (t, J=7.2 Hz, 6H).

Compound 24: 4-(2-propylpentanoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-propylpentanoate (500 mg, 2.31 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (160 mg, 30%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.12 (t, J=6.0 Hz, 2H), 2.46 (t, J=7.6 Hz,2H), 2.41-2.31 (m, 1H), 2.01-1.95 (m, 2H), 1.63-1.54 (m, 2H), 1.45-1.37(m, 2H), 1.33-1.24 (m, 4H), 0.89 (t, J=7.2 Hz, 6H).

Example 1-25 Intermediate Compound 25′: 4-hydroxybutylcyclopentanecarboxylate

A solution of cyclopentanecarbonyl chloride (528 mg, 4 mmol) in DCM (5mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-3:1to yield the titled compound (520 mg, 70%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=4.10 (t, J=6.4 Hz, 2H), 3.68(t, J=6.0 Hz, 2H), 2.76-2.68 (m, 1H), 1.92-1.62 (m, 10H), 1.60-1.53 (m,2H), 1.41 (br. s., 1H).

Compound 25: 4-(cyclopentanecarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl cyclopentanecarboxylate (450 mg, 2.42 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=3:1 to yield thetitled compound (373 mg, 77%) as colorless oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.12 (t, J=6.2 Hz, 2H), 2.76-2.68 (m, 1H),2.45 (t, J=7.2 Hz, 2H), 2.01-1.94 (m, 2H), 1.92-1.84 (m, 2H), 1.82-1.65(m, 4H), 1.61-1.50 (m, 2H).

Example 1-26 Intermediate Compound 26′: 4-hydroxybutylcyclohexanecarboxylate

A solution of cyclohexanecarbonyl chloride (584 mg, 4 mmol) in DCM (5mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-3:1to yield the titled compound (440 mg, 55%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=4.08 (t, J=6.2 Hz, 2H), 3.66(t, J=6.2 Hz, 2H), 2.32-2.24 (m, 1H), 1.88 (d, J=13.2 Hz, 2H), 1.76-1.58(m, 8H), 1.48-1.37 (m, 2H), 1.31-1.15 (m, 3H).

Compound 26: 4-(cyclohexanecarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl cyclohexanecarboxylate (400 mg, 2 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=3:1 to yield thetitled compound (350 mg, 82%) as colorless oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.11 (t, J=6.4 Hz, 2H), 2.45 (t, J=7.4 Hz,2H), 2.29 (tt, J=3.6, 11.3 Hz, 1H), 2.01-1.94 (m, 2H), 1.91-1.87 (m,2H), 1.76-1.69 (m, 2H), 1.65-1.62 (m, 1H), 1.48-1.38 (m, 2H), 1.33-1.19(m, 3H).

Example 1-27 Intermediate Compound 27′: 4-hydroxybutyl 2-acetoxyacetate

A solution of 2-chloro-2-oxoethyl acetate (544 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=8:1-5:1 toyield the titled compound (500 mg, 66%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=4.60 (s, 2H), 4.22 (t, J=6.4 Hz,2H), 3.68 (dd, J=5.8, 10.6 Hz, 2H), 2.16 (s, 3H), 1.81-1.72 (m, 2H),1.68-1.60 (m, 2H), 1.39 (br. s., 1H).

Compound 27: 4-(2-acetoxyacetoxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-acetoxyacetate (400 mg, 2.11 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=8:1-3:1 to yield thetitled compound (370 mg, 86%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.60 (s, 2H), 4.24 (t, J=6.2 Hz, 2H), 2.46 (t,J=7.4 Hz, 2H), 2.16 (s, 3H), 2.04-1.97 (m, 2H).

Example 1-28 Intermediate Compound 28′: ethyl (4-hydroxybutyl) carbonate

A solution of ethyl carbonochloridate (1 g, 9.17 mmol) in DCM (5 mL) wasadded dropwise during 10 min to a stirred solution of butane-1,4-diol(1659 mg, 18.43 mmol) and Et₃N (1861 mg, 18.43 mmol) in DCM (10 mL) at0° C. The reaction was allowed to warm up gradually and stirred at 0-25°C. over 16 h. After that, the reaction mixture was diluted with H₂O (5mL) and stirred for 5 min. The aqueous phase was separated and extractedwith DCM (5 mL). The combined organic phase was washed with saturatedbrine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (700 mg, 47%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.22-4.16 (m, 4H), 3.68 (q, J=5.8 Hz, 2H),1.81-1.74 (m, 2H), 1.69-1.62 (m, 2H), 1.38 (t, J=5.0 Hz, 1H), 1.31 (t,J=7.0 Hz, 3H).

Compound 28: 4-(ethoxycarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of ethyl(4-hydroxybutyl) carbonate (500 mg, 3.09 mmol) and Celite® (diatomaceousearth, 2 g) in acetone (10 mL) at 0° C. The reaction proceeded at 0° C.for over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of iPrOH, diluted withEA (10 mL) and then filtered. The filtered cake was washed with EA (5mL) and the combined filtrate was washed with saturated brine (2 mL×2),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby a silica gel flash column with Hex/EA=10:1-5:1 to yield the titledcompound (70 mg, 13%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=4.22-4.17 (m, 4H), 2.50 (t, J=7.2 Hz, 2H), 2.05-1.98(m, 2H), 1.31 (t, J=7.2 Hz, 3H).

Example 1-29 Intermediate Compound 29′: 4-hydroxybutyl isopropylcarbonate

A solution of isopropyl carbonochloridate (10 ml, 1.0 M/L, 10 mmol) inDCM (10 mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (1800 mg, 20 mmol) and Et₃N (2020 mg, 20 mmol) in DCM(20 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 16 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=5:1 to yield the titled compound (1.58 g, 90%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=4.90-4.84(m, 1H), 4.16 (t, J=6.6 Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 1.80-1.73 (m,2H), 1.69-1.62 (m, 2H), 1.29 (d, J=5.6 Hz, 6H).

Compound 29: 4-(isopropoxycarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl isopropyl carbonate (800 mg, 4.55 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (260 mg, 30%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.90-4.84 (m, 1H), 4.18 (t, J=6.2 Hz, 2H),2.50 (t, J=7.2 Hz, 2H), 2.05-1.97 (m, 2H), 1.30 (d, J=6.0 Hz, 6H).

Example 1-30 Intermediate Compound 30′: 4-hydroxybutyl isobutylcarbonate

A solution of isobutyl carbonochloridate (544 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-6:1to yield the titled compound (250 mg, 33%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=4.18 (t, J=6.4 Hz, 2H), 3.91(d, J=6.8 Hz, 2H), 3.69 (dd, J=5.4, 11.0 Hz, 2H), 1.81-1.75 (m, 3H),1.70-1.62 (m, 2H), 0.96 (s, 3H), 0.94 (s, 3H).

Compound 30: 4-(isobutoxycarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl isobutyl carbonate (200 mg, 1.1 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=8:1-3:1 to yield thetitled compound (110 mg, 51%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.20 (t, J=6.4 Hz, 2H), 3.92 (d, J=6.8 Hz,2H), 2.49 (t, J=7.2 Hz, 2H), 2.06-1.93 (m, 3H), 0.96 (s, 3H), 0.94 (s,3H).

Example 1-31 Intermediate Compound 31′: benzyl (4-hydroxybutyl)carbonate

A solution of benzyl carbonochloridate (1 g, 5.86 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (1055 mg, 11.72 mmol) and Et₃N (1184 mg, 11.72 mmol) inDCM (10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 3 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=7:1 to yield the titled compound (292 mg, 22%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.40-7.32(m, 5H), 5.16 (s, 2H), 4.20 (t, J=6.6 Hz, 2H), 3.68 (q, J=6.0 Hz, 2H),1.81-1.74 (m, 2H), 1.68-1.62 (m, 2H), 1.29 (t, J=5.4 Hz, 1H).

Compound 31: 4-(benzyloxycarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of benzyl(4-hydroxybutyl) carbonate (290 mg, 1.29 mmol) and Celite® (diatomaceousearth, 2 g) in acetone (10 mL) at 0° C. The reaction proceeded at 0° C.for over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of iPrOH, diluted withEA (10 mL) and then filtered. The filtered cake was washed with EA (5mL) and the combined filtrate was washed with saturated brine (2 mL×2),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby a silica gel flash column with Hex/EA=10:1-5:1 to yield the titledcompound (188 mg, 61%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=7.38-7.33 (m, 5H), 5.16 (s, 2H), 4.21 (t, J=6.2 Hz,2H), 2.47 (t, J=7.2 Hz, 2H), 2.03-1.97 (m, 2H).

Example 1-32 Intermediate Compound 32′: 4-hydroxybutyl phenyl carbonate

A solution of phenyl carbonochloridate (624 mg, 4 mmol) in DCM (5 mL)was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (450 mg, 5 mmol) and Et₃N (505 mg, 5 mmol) in DCM (5 mL)at 0° C. The reaction was allowed to warm up gradually and stirred at0-25° C. for over 1 h. After that, the reaction mixture was diluted withH₂O (5 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (5 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=10:1-5:1to yield the titled compound (333 mg, 40%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.39 (t, J=7.8 Hz, 2H),7.26-7.23 (m, 1H), 7.18 (d, J=8.0 Hz, 2H), 4.30 (t, J=6.6 Hz, 2H), 3.72(dd, J=6.2, 11.2 Hz, 2H), 1.89-1.82 (m, 2H), 1.75-1.68 (m, 2H), 1.35 (t,J=5.2 Hz, 1H).

Compound 32: 4-(phenoxycarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl phenyl carbonate (300 mg, 1.55 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-2:1 to yield thetitled compound (210 mg, 65%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.39 (t, J=8.0 Hz, 2H), 7.25 (t, J=7.2 Hz,1H), 7.18 (d, J=8.0 Hz, 2H), 4.32 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.4 Hz,2H), 2.13-2.06 (m, 2H).

Example 1-33 Intermediate Compound 33′: 4-chlorophenyl (4-hydroxybutyl)carbonate

A solution of 4-chlorophenyl carbonochloridate (500 mg, 2.62 mmol) inDCM (5 mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (707 mg, 7.86 mmol) and Et₃N (529 mg, 5.24 mmol) in DCM(10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 16 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=6:1 to yield the titled compound (420 mg, 66%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.35 (d,J=9.2 Hz, 2H), 7.13 (d, J=9.2 Hz, 2H), 4.30 (t, J=6.4 Hz, 2H), 3.72 (t,J=6.2 Hz, 2H), 1.89-1.82 (m, 2H), 1.74-1.67 (m, 2H).

Compound 33: 4-((4-chlorophenoxy)carbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-chlorophenyl (4-hydroxybutyl) carbonate (400 mg, 1.64 mmol) andCelite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column withHex/EA=10:1-5:1 to yield the titled compound (220 mg, 52%) as a whitesolid. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.35 (d,J=9.2 Hz, 2H), 7.13 (d, J=8.8 Hz, 2H), 4.32 (t, J=6.2 Hz, 2H), 2.55 (t,J=7.4 Hz, 2H), 2.13-2.06 (m, 2H).

Example 1-34 Intermediate Compound 34′: 4-hydroxybutyl p-tolyl carbonate

A solution of p-tolyl carbonochloridate (500 mg, 2.94 mmol) in DCM (5mL) was added dropwise during 10 min to a stirred solution ofbutane-1,4-diol (794 mg, 8.82 mmol) and Et₃N (594 mg, 5.88 mmol) in DCM(10 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 16 h. After that, the reaction mixture wasdiluted with H₂O (5 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with saturated brine (5 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=6:1 to yield the titled compound (600 mg, 91%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.17 (d,J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 4.29 (t, J=6.8 Hz, 2H), 3.72 (t,J=6.2 Hz, 2H), 2.34 (s, 3H), 1.89-1.82 (m, 2H), 1.74-1.67 (m, 2H).

Compound 34: 4-(p-tolyloxycarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl p-tolyl carbonate (500 mg, 2.23 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (170 mg, 32%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.17 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.0 Hz,2H), 4.31 (t, J=6.2 Hz, 2H), 2.55 (t, J=7.2 Hz, 2H), 2.34 (s, 3H),2.12-2.07 (m, 2H).

Example 1-35 Intermediate Compound 35′: 4-hydroxybutyl 4-butoxybenzoate

4-butoxybenzoic acid (882 mg, 4.55 mmol), DCC (1030 mg, 5 mmol) and DMAP(50 mg) was added to a stirred solution of butane-1,4-diol (450 mg, 5mmol) in DCM (15 mL). The reaction was stirred at 25° C. for 3 h. Afterthat, the reaction mixture was diluted with saturated aqueous NH₄Cl (10mL) and stirred for 5 min. The aqueous phase was separated and extractedwith DCM (5 mL). The combined organic phase was washed with saturatedbrine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (500 mg, 41%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.97 (d, J=8.4 Hz, 2H), 6.90 (d, J=9.2 Hz,2H), 4.33 (t, J=6.2 Hz, 2H), 4.01 (t, J=6.6 Hz, 2H), 3.73 (t, J=6.4 Hz,2H), 1.89-1.71 (m, 6H), 1.61 (br. s., 1H), 1.54-1.45 (m, 2H), 0.98 (t,J=7.2 Hz, 3H).

Compound 35: 4-(4-butoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-butoxybenzoate (450 mg, 1.69 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (200 mg, 42%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.97 (d, J=8.8 Hz, 2H), 6.90 (d,J=8.8 Hz, 2H), 4.35 (t, J=6.2 Hz, 2H), 4.01 (t, J=6.4 Hz, 2H), 2.54 (t,J=7.2 Hz, 2H), 2.14-2.07 (m, 2H), 1.82-1.75 (m, 2H), 1.53-1.46 (m, 2H),0.98 (t, J=7.4 Hz, 3H).

Example 1-36 Intermediate Compound 36′: 4-hydroxybutyl4-isopropylbenzoate

4-isopropylbenzoic acid (745 mg, 4.54 mmol), DCC (1030 mg, 5 mmol) andDMAP (50 mg) was added to a stirred solution of butane-1,4-diol (450 mg,5 mmol) in DCM (15 mL). The reaction was stirred at 25° C. for 3 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=5:1 toyield the titled compound (400 mg, 37%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.96 (d, J=8.0 Hz, 2H), 7.29 (d,J=8.0 Hz, 2H), 4.35 (t, J=6.4 Hz, 2H), 3.76-3.69 (m, 2H), 2.99-2.93 (m,1H), 1.90-1.83 (m, 2H), 1.76-1.69 (m, 2H), 1.40 (br. s., 1H), 1.27 (s,3H), 1.26 (s, 3H).

Compound 36: 4-(4-isopropylbenzoyloxy) butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-isopropylbenzoate (350 mg, 1.48 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (200 mg, 54%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.95 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.4 Hz,2H), 4.37 (t, J=6.2 Hz, 2H), 2.99-2.92 (m, 1H), 2.54 (t, J=7.4 Hz, 2H),2.15-2.08 (m, 2H), 1.27 (s, 3H), 1.25 (s, 3H).

Example 1-37 Intermediate Compound 37′: 4-hydroxybutyl3-(methylsulfonyl)benzoate

3-(methylsulfonyl) benzoic acid (505 mg, 2.53 mmol), DCC (572 mg, 2.78mmol) and DMAP (50 mg) was added to a stirred solution ofbutane-1,4-diol (250 mg, 2.78 mmol) in DCM (15 mL). The reaction wasstirred at 25° C. for 3 h. After that, the reaction mixture was dilutedwith saturated aqueous NH₄Cl (10 mL) and stirred for 5 min. The aqueousphase was separated and extracted with DCM (5 mL). The combined organicphase was washed with saturated brine (10 mL), dried over anhydrousNa₂SO₄ and evaporated. The residue was purified by a silica gel flashcolumn with Hex/EA=2:1 to yield the titled compound (150 mg, 22%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=8.60 (s,1H), 8.33 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.69 (t, J=7.8 Hz,1H), 4.42 (t, J=6.6 Hz, 2H), 3.74 (q, J=6.0 Hz, 2H), 3.10 (s, 3H),1.94-1.87 (m, 2H), 1.76-1.70 (m, 2H), 1.36 (t, J=5.0 Hz, 1H).

Compound 37: 4-(3-(methylsulfonyl)benzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-(methylsulfonyl)benzoate (150 mg, 0.55 mmol) andCelite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column with Hex/EA=2:1 toyield the titled compound (70 mg, 44%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=8.59 (s, 1H), 8.32 (d, J=8.0 Hz,1H), 8.15 (d, J=8.0 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 4.44 (t, J=6.2 Hz,2H), 3.11 (s, 3H), 2.55 (t, J=7.0 Hz, 2H), 2.20-2.14 (m, 2H).

Example 1-38 Intermediate Compound 38′: 4-hydroxybutyl nicotinate

Nicotinic acid (615 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) and DMAP (50mg) was added to a stirred solution of butane-1,4-diol (900 mg, 10 mmol)in DCM (15 mL). The reaction was stirred at 25° C. for 16 h. After that,the reaction mixture was diluted with saturated aqueous NH₄Cl (10 mL)and stirred for 5 min. The aqueous phase was separated and extractedwith DCM (5 mL). The combined organic phase was washed with saturatedbrine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=1:1 to yield thetitled compound (450 mg, 46%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=9.22 (d, J=1.6 Hz, 1H), 8.78 (dd, J=1.6, 4.8Hz, 1H), 8.30 (td, J=1.6, 8.0 Hz, 1H), 7.40 (dd, J=5.0, 7.8 Hz, 1H),4.41 (t, J=6.6 Hz, 2H), 3.74 (t, J=6.2 Hz, 2H), 1.93-1.86 (m, 2H),1.77-1.70 (m, 2H), 1.46 (br. s., 1H).

Compound 38: 4-(nicotinoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl nicotinate (450 mg, 2.31 mmol) and Celite® (diatomaceousearth, 2 g) in acetone (10 mL) at 0° C. The reaction proceeded at 0° C.for over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of iPrOH, diluted withEA (10 mL) and then filtered. The filtered cake was washed with EA (5mL) and the combined filtrate was washed with saturated brine (2 mL×2),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby a silica gel flash column with Hex/EA=1:1 to yield the titledcompound (50 mg, 10%) as crystalline solids. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=9.21 (d, J=1.6 Hz, 1H), 8.72 (dd, J=1.2, 4.8 Hz, 1H),8.33 (td, J=1.6, 7.6 Hz, 1H), 7.40 (dd, J=5.0, 7.8 Hz, 1H), 4.45 (t,J=6.2 Hz, 2H), 2.56 (t, J=7.0 Hz, 2H), 2.21-2.15 (m, 2H).

Example 1-39 Intermediate Compound 39′: 4-hydroxybutyl isonicotinate

Isonicotinic acid (1.23 g, 10 mmol), DCC (2.27 g, 11 mmol) and DMAP (122mg) was added to a stirred solution of butane-1,4-diol (2.7 g, 30 mmol)in DCM (30 mL). The reaction was stirred at 25° C. for 8 h. After that,the reaction mixture was diluted with saturated aqueous NH₄Cl (10 mL)and stirred for 5 min. The aqueous phase was separated and extractedwith DCM (15 mL). The combined organic phase was washed with brine (10mL), dried over Na₂SO₄ and evaporated. The residue was purified by asilica gel flash column with Hex/EA=10:1-2:1 to yield the titledcompound (1 g, 51%) as a pale yellow oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=8.76 (d, J=8.4 Hz, 2H), 7.84 (d, J=5.6 Hz, 2H), 4.39(t, J=6.4 Hz, 2H), 3.72 (t, J=6.2 Hz, 2H), 1.92-1.85 (m, 2H), 1.75-1.70(m, 2H).

Compound 39: 4-(isonicotinoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl isonicotinate (900 mg, 4.62 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (30 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (50 mL) and then filtered. The filtered cake was washedwith EA (50 mL) and the combined filtrate was washed with brine (5mL×2), dried over Na₂SO₄ and concentrated. The residue was purified by asilica gel flash column with Hex/EA=2:1 to yield the titled compound (70mg, 7%) as a white solid. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=8.55 (d, J=6.0 Hz, 2H), 7.86 (d, J=6.4 Hz, 2H), 4.49 (t, J=5.8 Hz,2H), 2.53 (t, J=6.6 Hz, 2H), 2.23-2.17 (m, 2H).

Example 1-40 Intermediate Compound 40′: 4-hydroxybutyl3-methoxy-4-methylbenzoate

3-methoxy-4-methylbenzoic acid (500 mg, 3 mmol), DCC (683 mg, 3.32 mmol)and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (542mg, 6 mmol) in DCM (15 mL). The reaction was stirred at 25° C. for 3 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=5:1 toyield the titled compound (450 mg, 63%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.55 (d, J=7.6 Hz, 1H), 7.48 (s,1H), 7.18 (d, J=8.0 Hz, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.88 (s, 3H), 3.73(t, J=6.2 Hz, 2H), 2.26 (s, 3H), 1.91-1.84 (m, 2H), 1.76-1.70 (m, 2H).

Compound 40: 4-(3-methoxy-4-methylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 3-methoxy-4-methylbenzoate (450 mg, 1.89 mmol) andCelite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column with Hex/EA=4:1 toyield the titled compound (280 mg, 59%) as crystalline solids. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.54 (d, J=7.6 Hz, 1H), 7.47(s, 1H), 7.18 (d, J=7.6 Hz, 1H), 4.37 (t, J=6.2 Hz, 2H), 3.88 (s, 3H),2.54 (t, J=7.4 Hz, 2H), 2.26 (s, 3H), 2.15-2.09 (m, 2H).

Example 1-41 Intermediate Compound 41′: 4-hydroxybutyl2,6-dimethylbenzoate

2,6-dimethylbenzoic acid (500 mg, 3.33 mmol), DCC (755 mg, 3.67 mmol)and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (600mg, 6.67 mmol) in DCM (15 mL). The reaction was stirred at 25° C. for 3h. After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withsaturated brine (10 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=5:1 toyield the titled compound (100 mg, 14%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.18 (t, J=7.6 Hz, 1H), 7.03 (d,J=8.0 Hz, 2H), 4.37 (t, J=6.6 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 2.32 (s,6H), 1.89-1.82 (m, 2H), 1.74-1.67 (m, 2H).

Compound 41: 4-(2,6-dimethylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2,6-dimethylbenzoate (100 mg, 0.45 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (50 mg, 47%) as a colorless oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.19 (t, J=7.4 Hz, 1H), 7.03 (d, J=7.6 Hz,2H), 4.39 (t, J=6.4 Hz, 2H), 2.52 (t, J=7.4 Hz, 2H), 2.32 (s, 6H),2.13-2.07 (m, 2H).

Example 1-42 Intermediate Compound 42′: 4-hydroxybutyl 2-phenoxybenzoate

2-phenoxybenzoic acid (1070 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) andDMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg,10 mmol) in DCM (30 mL). The reaction was stirred at 25° C. for 16 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (10 mL). The combined organic phase was washed withsaturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=8:1 toyield the titled compound (700 mg, 49%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.93 (dd, J=1.6, 8.0 Hz, 1H),7.50-7.45 (m, 1H), 7.32 (t, J=7.8 Hz, 2H), 7.21 (t, J=7.6 Hz, 1H), 7.07(t, J=7.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.94 (d, J=7.6 Hz, 2H), 4.26(t, J=6.2 Hz, 2H), 3.58 (s, 2H), 1.72-1.65 (m, 2H), 1.58-1.51 (m, 2H).

Compound 42: 4-(2-phenoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-phenoxybenzoate (700 mg, 2.45 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (400 mg, 54%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.92 (dd, J=1.6, 7.6 Hz, 1H), 7.50-7.46 (m,1H), 7.31 (d, J=8.0 Hz, 2H), 7.20 (t, J=7.6 Hz, 1H), 7.07 (t, J=7.4 Hz,1H), 7.00 (d, J=8.4 Hz, 1H), 6.93 (d, J=8.0 Hz, 2H), 4.27 (t, J=6.2 Hz,2H), 2.36 (t, J=7.2 Hz, 2H), 1.96-1.90 (m, 2H).

Example 1-43 Intermediate Compound 43′: 4-hydroxybutyl2,4-dimethylbenzoate

2,4-dimethylbenzoic acid (750 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) andDMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg,10 mmol) in DCM (30 mL). The reaction was stirred at 25° C. for 16 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (10 mL). The combined organic phase was washed withsaturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=8:1 toyield the titled compound (700 mg, 63%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.82 (d, J=7.6 Hz, 1H), 7.05-7.03(m, 2H), 4.32 (t, J=6.6 Hz, 2H), 3.73 (s, 2H), 2.57 (s, 3H), 2.35 (s,3H), 1.89-1.82 (m, 2H), 1.76-1.69 (m, 2H).

Compound 43: 4-(2,4-dimethylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2,4-dimethylbenzoate (700 mg, 3.15 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (550 mg, 74%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.82 (d, J=7.6 Hz, 1H), 7.05-7.03 (m, 2H),4.34 (t, J=6.2 Hz, 2H), 2.57 (s, 3H), 2.54 (t, J=7.4 Hz, 2H), 2.35 (s,3H), 2.14-2.08 (m, 2H).

Example 1-44 Intermediate Compound 44′: 4-hydroxybutyl2,3-dimethoxybenzoate

2,3-dimethoxybenzoic acid (910 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) andDMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg,10 mmol) in DCM (30 mL). The reaction was stirred at 25° C. for 16 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (10 mL). The combined organic phase was washed withsaturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=8:1 toyield the titled compound (600 mg, 47%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.32 (dd, J=1.6, 7.2 Hz, 1H),7.11-7.04 (m, 2H), 4.36 (t, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H),3.74-3.70 (m, 2H), 1.90-1.84 (m, 2H), 1.77-1.70 (m, 2H), 1.40 (t, J=4.8Hz, 1H).

Compound 44: 4-(2,3-dimethoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2,3-dimethoxybenzoate (600 mg, 2.36 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (250 mg, 39%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.31 (dd, J=2.0, 7.2 Hz, 1H), 7.11-7.05 (m,2H), 4.38 (t, J=6.2 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.57 (t, J=7.4Hz, 2H), 2.15-2.08 (m, 2H).

Example 1-45 Intermediate Compound 45′: 4-hydroxybutyl4-isopropoxybenzoate

4-isopropoxybenzoic acid (900 mg, 5 mmol), DCC (1133 mg, 5.5 mmol) andDMAP (50 mg) was added to a stirred solution of butane-1,4-diol (900 mg,10 mmol) in DCM (30 mL). The reaction was stirred at 25° C. for 16 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (10 mL). The combined organic phase was washed withsaturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=6:1 toyield the titled compound (800 mg, 63%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.97 (d, J=8.8 Hz, 2H), 6.88 (d,J=9.2 Hz, 2H), 4.66-4.60 (m, 1H), 4.33 (t, J=6.4 Hz, 2H), 3.73 (q, J=6.0Hz, 2H), 1.89-1.82 (m, 2H), 1.76-1.69 (m, 2H), 1.37 (s, 3H), 1.35 (s,3H).

Compound 45: 4-(4-isopropoxybenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-isopropoxybenzoate (800 mg, 3.17 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (380 mg, 45%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.96 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz,2H), 4.66-4.60 (m, 1H), 4.35 (t, J=6.2 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H),2.15-2.08 (m, 2H), 1.37 (s, 3H), 1.35 (s, 3H).

Example 1-46 Intermediate Compound 46′: 4-hydroxybutyl 2-ethylbenzoate

2,6-dimethylbenzoic acid (500 mg, 3.33 mmol), DCC (755 mg, 3.67 mmol)and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol (600mg, 6.67 mmol) in DCM (30 mL). The reaction was stirred at 25° C. for 3h. After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (10 mL). The combined organic phase was washed withsaturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=8:1 toyield the titled compound (480 mg, 65%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.84 (d, J=8.0 Hz, 1H), 7.43 (t,J=7.4 Hz, 1H), 7.28-7.22 (m, 2H), 4.34 (t, J=6.6 Hz, 2H), 3.73 (t, J=6.0Hz, 2H), 2.98 (q, J=7.6 Hz, 2H), 1.91-1.84 (m, 2H), 1.77-1.70 (m, 2H),1.24 (t, J=7.4 Hz, 3H).

Compound 46: 4-(2-ethylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-ethylbenzoate (480 mg, 2.16 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=6:1 to yield thetitled compound (290 mg, 57%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.84 (d, J=8.0 Hz, 1H), 7.43 (d, J=7.2 Hz,1H), 7.29-7.22 (m, 2H), 4.36 (t, J=6.2 Hz, 2H), 2.98 (q, J=7.6 Hz, 2H),2.55 (t, J=7.2 Hz, 2H), 2.15-2.08 (m, 2H), 1.24 (t, J=7.6 Hz, 3H).

Example 1-47 Intermediate Compound 47′: 4-hydroxybutyl 4-benzoylbenzoate

4-benzoylbenzoic acid (500 mg, 2.21 mmol), DCC (501 mg, 2.44 mmol) andDMAP (5 mg) was added to a stirred solution of butane-1,4-diol (398 mg,4.42 mmol) in DCM (30 mL). The reaction was stirred at 25° C. for 3 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (10 mL). The combined organic phase was washed withsaturated brine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with Hex/EA=6:1 toyield the titled compound (400 mg, 61%) as a white solid. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=8.15 (d, J=8.4 Hz, 2H), 7.85-7.80(m, 4H), 7.62 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 2H), 4.41 (t, J=6.4Hz, 2H), 3.75 (t, J=6.4 Hz, 2H), 1.94-1.87 (m, 2H), 1.79-1.72 (m, 2H).

Compound 47: 4-(4-benzoylbenzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 4-benzoylbenzoate (400 mg, 1.34 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (280 mg, 67%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=8.14 (d, J=8.4 Hz, 2H), 7.85-7.80 (m, 4H),7.62 (t, J=7.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 2H), 4.44 (t, J=6.2 Hz, 2H),2.57 (t, J=7.2 Hz, 2H), 2.19-2.12 (m, 2H).

Example 1-48 Intermediate Compound 48′: 4-hydroxybutyl methyl phthalate

2-(methoxycarbonyl)benzoic acid (900 mg, 5 mmol), DCC (1.13 g, 5.5 mmol)and DMAP (60 mg) was added to a stirred solution of butane-1,4-diol(1.35 g, 15 mmol) in DCM (30 mL). The reaction was stirred at 25° C. for3 h. After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (15 mL). The combined organic phase was washed withbrine (10 mL), dried over Na₂SO₄ and evaporated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-2:1 to yield thetitled compound (1 g, 79%) as a colorless oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.72-7.68 (m, 2H), 7.55-7.51 (m, 2H), 4.34 (t,J=6.6 Hz, 2H), 3.89 (s, 3H), 3.68 (t, J=6.4 Hz, 2H), 1.83-1.77 (m, 3H),1.70-1.65 (m, 2H).

Compound 48: 4-(2-(methoxycarbonyl)benzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl methyl phthalate (900 mg, 3.57 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (20 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (10 mL) and the combined filtrate was washed with brine (3mL×2), dried over Na₂SO₄ and concentrated. The residue was purified by asilica gel flash column with Hex/EA=10:1-1:1 to yield the titledcompound (800 mg, 84%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=7.74-7.70 (m, 2H), 7.55-7.53 (m, 2H), 4.37 (t, J=6.2Hz, 2H), 3.91 (s, 3H), 2.51 (t, J=7.2 Hz, 2H), 2.10-2.03 (m, 2H).

Example 1-49 Intermediate Compound 49′: 4-hydroxybutyl methylterephthalate

4-(methoxycarbonyl)benzoic acid (1 g, 5.56 mmol), DCC (1258 mg, 6.11mmol) and DMAP (10 mg) was added to a stirred solution ofbutane-1,4-diol (1.5 g, 16.67 mmol) in DCM (20 mL). The reaction wasstirred at 25° C. for 16 h. After that, the reaction mixture was dilutedwith saturated aqueous NH₄Cl (10 mL) and stirred for 5 min. The aqueousphase was separated and extracted with DCM (5 mL). The combined organicphase was washed with brine (10 mL), dried over Na₂SO₄ and evaporated.The residue was purified by a silica gel flash column with Hex/EA=7:1 toyield the titled compound (750 mg, 54%) as crystalline solids. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=8.10 (s, 4H), 4.39 (t, J=6.6Hz, 2H), 3.95 (s, 3H), 3.74 (t, J=6.4 Hz, 2H), 1.92-1.87 (m, 2H),1.77-1.72 (m, 2H).

Compound 49: 4-(4-(methoxycarbonyl)benzoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl methyl terephthalate (700 mg, 2.78 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with brine (2 mL×2),dried over Na₂SO₄ and concentrated. The residue was purified by a silicagel flash column with Hex/EA=7:1 to yield the titled compound (400 mg,54%) as crystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃as solvent to characterize the titled compound, results are as follows:δ=8.09 (s, 4H), 4.41 (t, J=6.2 Hz, 2H), 3.95 (s, 3H), 2.55 (t, J=7.2 Hz,2H), 2.18-2.11 (m, 2H).

Example 1-50 Intermediate Compound 50′: 4-hydroxybutyl (²H₅)benzoate

(²H₅) benzoic acid (300 mg, 2.36 mmol), DCC (535 mg, 2.6 mmol) and DMAP(10 mg) was added to a stirred solution of butane-1,4-diol (425 mg, 4.72mmol) in DCM (20 mL). The reaction was stirred at 25° C. for 16 h. Afterthat, the reaction mixture was diluted with saturated aqueous NH₄Cl (10mL) and stirred for 5 min. The aqueous phase was separated and extractedwith DCM (10 mL). The combined organic phase was washed with saturatedbrine (15 mL), dried over anhydrous Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=5:1 to yield thetitled compound (320 mg, 68%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.37 (t, J=6.4 Hz, 2H), 3.74 (t, J=6.4 Hz,2H), 1.91-1.84 (m, 2H), 1.78-1.71 (m, 2H).

Compound 50: 4-((²H₅)phenylcarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl (²H₅)benzoate (300 mg, 1.51 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (220 mg, 69%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=4.39 (t, J=6.2 Hz, 2H), 2.56 (t, J=7.4 Hz,2H), 2.17-2.10 (m, 2H).

Example 1-51 Intermediate Compound 51′: 4-hydroxybutylthiazole-2-carboxylate

Thiazole-2-carboxylic acid (500 mg, 3.88 mmol), DCC (879 mg, 4.27 mmol)and DMAP (50 mg) was added to a stirred solution of butane-1,4-diol(1.05 g, 11.66 mmol) in DCM (10 mL). The reaction was stirred at 25° C.for 8 h. After that, the reaction mixture was diluted with saturatedaqueous NH₄Cl (10 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (5 mL). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=10:1-2:1 to yieldthe titled compound (300 mg, 38%) as a pale yellow oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=8.03 (d, J=2.8 Hz, 1H), 7.64 (d,J=3.2 Hz, 1H), 4.47 (t, J=6.6 Hz, 2H), 3.73 (t, J=6.2 Hz, 2H), 1.97-1.90(m, 2H), 1.77-1.70 (m, 2H).

Compound 51: 4-(thiazole-2-carbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl thiazole-2-carboxylate (300 mg, 1.49 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with brine (2 mL×2),dried over Na₂SO₄ and concentrated. The residue was purified by a silicagel flash column with Hex/EA=10:1-1:1 to yield the titled compound (200mg, 62%) as crystalline solids. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=8.06 (d, J=2.8 Hz, 1H), 7.67 (d, J=3.2 Hz, 1H), 4.49 (t,J=6.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 2.19-2.12 (m, 2H).

Example 1-52 Intermediate Compound 52′: 4-hydroxybutylfuran-3-carboxylate

Furan-3-carboxylic acid (224 mg, 2 mmol), DCC (453 mg, 2.2 mmol) andDMAP (24 mg) was added to a stirred solution of butane-1,4-diol (540 mg,6 mmol) in DCM (10 mL). The reaction was stirred at 25° C. for 12 h.After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withbrine (10 mL), dried over Na₂SO₄ and evaporated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (270 mg, 73%) as a pale yellow oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=8.00 (s, 1H), 7.42 (s, 1H), 6.73 (s, 1H), 4.28(t, J=6.4 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H), 1.83-1.67 (m, 4H).

Compound 52: 4-(furan-3-carbonyloxy)butanoic acid

Jones reagent in portions was added to a stirred mixture of4-hydroxybutyl furan-3-carboxylate (750 mg, 4.09 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with brine (2 mL×2),dried over Na₂SO₄ and concentrated. The residue was purified by a silicagel flash column with Hex/EA=3:1 to yield the titled compound (600 mg,74%) as crystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃as solvent to characterize the titled compound, results are as follows:δ=8.01 (s, 1H), 7.42 (s, 1H), 6.73 (s, 1H), 4.31 (t, J=6.2 Hz, 2H), 2.51(t, J=7.4 Hz, 2H), 2.12-2.05 (m, 2H).

Example 1-53 Intermediate Compound 53′: 4-hydroxybutylthiophene-3-carboxylate

Thiophene-3-carboxylic acid (1 g, 7.81 mmol), DCC (1.77 g, 8.59 mmol)and DMAP (10 mg) was added to a stirred solution of butane-1,4-diol (2.1g, 23.33 mmol) in DCM (50 mL). The reaction was stirred at 25° C. for 16h. After that, the reaction mixture was diluted with saturated aqueousNH₄Cl (10 mL) and stirred for 5 min. The aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withbrine (10 mL), dried over Na₂SO₄ and evaporated. The residue waspurified by a silica gel flash column with Hex/EA=7:1 to afford thecrude product, which was further purified by prep-TLC with Hex/EA=1:1 toyield the pure titled compound (600 mg, 38%) as crystalline solids. ¹HNMR was performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=8.10 (d, J=2.0 Hz, 1H), 7.53(d, J=5.2 Hz, 1H), 7.31 (dd, J=3.2, 5.2 Hz, 1H), 4.32 (t, J=6.4 Hz, 2H),3.73 (t, J=6.4 Hz, 2H), 1.90-1.80 (m, 2H), 1.76-1.68 (m, 2H).

Compound 53: 4-(thiophene-3-carbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl thiophene-3-carboxylate (400 mg, 2 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with brine (2 mL×2),dried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to yield the titled compound (100 mg, 23%) as crystallinesolids. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=8.10 (d,J=2.0 Hz, 1H), 7.52 (d, J=5.2 Hz, 1H), 7.31 (dd, J=3.0, 5.0 Hz, 1H),4.34 (t, J=6.2 Hz, 2H), 2.53 (t, J=7.2 Hz, 2H), 2.13-2.07 (m, 2H).

Example 1-54 Intermediate Compound 54′: (S)-1-tert-butyl2-(4-hydroxybutyl) pyrrolidine-1,2-dicarboxylate

(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2 g, 9.3mmol), DCC (2108 mg, 10.23 mmol) and DMAP (50 mg) was added to a stirredsolution of butane-1,4-diol (1674 mg, 18.6 mmol) in DCM (30 mL). Thereaction was stirred at 25° C. for 3 h. After that, the reaction mixturewas diluted with saturated aqueous NH₄Cl (10 mL) and stirred for 5 min.The aqueous phase was separated and extracted with DCM (10 mL). Thecombined organic phase was washed with saturated brine (15 mL), driedover anhydrous Na₂SO₄ and evaporated. The residue was purified by asilica gel flash column with Hex/EA=5:1 to yield the titled compound(1.4 g, 52%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=4.32-4.12 (m, 3H), 3.71-3.62 (m, 2H), 3.58-3.35 (m, 2H),2.27-2.16 (m, 1H), 2.02-1.60 (m, 8H), 1.46 (s, 4H), 1.41 (s, 5H).

Compound 54:(S)-4-(1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of(S)-1-tert-butyl 2-(4-hydroxybutyl) pyrrolidine-1,2-dicarboxylate (400mg, 1.39 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL)at 0° C. The reaction proceeded at 0° C. for over 1 h and the reactionprogress was monitored by TLC. After completion, the reaction wasquenched with drops of iPrOH, diluted with EA (10 mL) and then filtered.The filtered cake was washed with EA (5 mL) and the combined filtratewas washed with saturated brine (2 mL×2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash columnwith DCM/MeOH=120:1 to yield the titled compound (200 mg, 48%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=4.40-4.32(m, 1H), 4.26-4.07 (m, 2H), 3.58-3.35 (m, 2H), 2.45 (t, J=7.0 Hz, 2H),2.33-2.12 (m, 2H), 2.01-1.83 (m, 4H), 1.46 (s, 5H), 1.41 (s, 4H).

Example 1-55 Intermediate Compound 55′: 4-hydroxybutyl2-(tert-butoxycarbonylamino)acetate

2-(tert-butoxycarbonylamino)acetic acid (340 mg, 1.94 mmol), DCC (440mg, 2.14 mmol) and DMAP (5 mg) was added to a stirred solution ofbutane-1,4-diol (350 mg, 3.89 mmol) in DCM (30 mL). The reaction wasstirred at 25° C. for 16 h. After that, the reaction mixture was dilutedwith saturated aqueous NH₄Cl (10 mL) and stirred for 5 min. The aqueousphase was separated and extracted with DCM (10 mL). The combined organicphase was washed with saturated brine (15 mL), dried over anhydrousNa₂SO₄ and evaporated. The residue was purified by a silica gel flashcolumn with Hex/EA=5:1 to yield the titled compound (200 mg, 42%) as awhite solid. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.00 (br.s., 1H), 4.20 (t, J=6.6 Hz, 2H), 3.90 (d, J=5.2 Hz, 2H), 3.68 (q, J=6.0Hz, 2H), 1.79-1.72 (m, 2H), 1.67-1.62 (m, 2H), 1.45 (s, 9H), 1.37-1.34(m, 1H).

Compound 55: 4-(2-(tert-butoxycarbonylamino)acetoxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of4-hydroxybutyl 2-(tert-butoxycarbonylamino)acetate (200 mg, 0.81 mmol)and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a flash column (silica gel, DCM/MeOH=100:1to yield the titled compound (150 mg, 71%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=5.03 (br. s., 1H), 4.23 (t,J=6.2 Hz, 2H), 3.90 (d, J=5.2 Hz, 2H), 2.45 (t, J=7.2 Hz, 2H), 2.05-1.98(m, 2H), 1.45 (s, 9H).

Example 1-56 Compound 56: 4-(2-aminoacetoxy)butanoic acid

A solution of 4-(2-(tert-butoxycarbonylamino)acetoxy)butanoic acid (150mg, 0.57 mmol) in HCl/EA (˜2 M, 1.5 mL) was stirred at 25° C. for 24 h.After that, the reaction mixture was filtered and the resultingprecipitate was collected, washed with Et₂O (0.5 mL), dried in vacuo toyield the titled compound (82 mg, 89%) as a white solid in HCl saltform. ¹H NMR was performed at 400 MHz with CD₃OD as solvent tocharacterize the titled compound, results are as follows: δ=4.30 (t,J=6.4 Hz, 2H), 3.84 (s, 2H), 2.42 (t, J=7.2 Hz, 2H), 2.03-1.94 (m, 2H).

Example 1-57 Intermediate Compound 57′: (S)-4-hydroxybutyl2-(tert-butoxycarbonylamino)-3-phenylpropanoate

(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid (1 g, 3.37mmol), DCC (855 mg, 4.15 mmol) and DMAP (10 mg) was added to a stirredsolution of butane-1,4-diol (679 mg, 7.54 mmol) in DCM (20 mL). Thereaction was stirred at 25° C. for 16 h. After that, the reactionmixture was diluted with saturated aqueous NH₄Cl (10 mL) and stirred for5 min. The aqueous phase was separated and extracted with DCM (10 mL).The combined organic phase was washed with saturated brine (15 mL),dried over anhydrous Na₂SO₄ and evaporated. The residue was purified bya silica gel flash column with Hex/EA=5:1 to yield the titled compound(700 mg, 55%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=7.32-7.27 (m, 2H), 7.26-7.21 (m, 1H), 7.14 (d, J=6.8 Hz, 2H),4.97 (d, J=8.0 Hz, 1H), 4.58-4.53 (m, 1H), 4.19-4.08 (m, 2H), 3.64 (q,J=5.6 Hz, 2H), 3.07 (t, J=4.8 Hz, 2H), 1.72-1.65 (m, 2H), 1.56-1.51 (m,2H), 1.42 (s, 9H).

Intermediate Compound 57″:(S)-4-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (600mg, 1.78 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL)at 0° C. The reaction proceeded at 0° C. for over 1 h and the reactionprogress was monitored by TLC. After completion, the reaction wasquenched with drops of iPrOH, diluted with EA (10 mL) and then filtered.The filtered cake was washed with EA (5 mL) and the combined filtratewas washed with saturated brine (2 mL×2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash columnwith Hex/EA=10:1-5:1 to yield the titled compound (220 mg, 35%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.34-7.27(m, 2H), 7.26-7.20 (m, 1H), 7.14 (d, J=6.8 Hz, 2H), 4.99 (d, J=8.0 Hz,1H), 4.61-4.51 (m, 1H), 4.22-4.09 (m, 2H), 3.06 (d, J=6.0 Hz, 2H), 2.34(t, J=7.2 Hz, 2H), 1.97-1.89 (m, 2H), 1.42 (s, 9H).

Compound 57: (S)-4-(2-amino-3-phenylpropanoyloxy)butanoic acid

A solution of (S)-4-(2-(tert-butoxycarbonylamino)-3-phenylpropanoyloxy)butanoic acid (180 mg, 0.51 mmol) in HCl/EA (˜2 M, 2 mL) stirred at 25°C. for 24 h. After that, the reaction mixture was filtered and theresulting precipitate was collected, washed with Et₂O (0.5 mL), dried invacuo to yield the titled compound (100 mg, 78%) as a white solid in HClsalt form. ¹H NMR was performed at 400 MHz with CD₃OD as solvent tocharacterize the titled compound, results are as follows: δ=7.41-7.31(m, 3H), 7.27-7.25 (m, 2H), 4.30 (t, J=7.0 Hz, 1H), 4.26-4.19 (m, 2H),3.25-3.15 (m, 2H), 2.28 (t, J=7.2 Hz, 2H), 1.92-1.86 (m, 2H).

Example 1-58 Intermediate Compound 58′: (S)-4-hydroxybutyl2-(tert-butoxycarbonylamino)-3-methylbutanoate

(S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (1 g, 4.61 mmol),DCC (1044 mg, 5.07 mmol) and DMAP (10 mg) was added to a stirredsolution of butane-1,4-diol (829 mg, 9.21 mmol) in DCM (20 mL). Thereaction was stirred at 25° C. for 16 h. After that, the reactionmixture was diluted with saturated aqueous NH₄Cl (10 mL) and stirred for5 min. The aqueous phase was separated and extracted with DCM (10 mL).The combined organic phase was washed with saturated brine (15 mL),dried over anhydrous Na₂SO₄ and evaporated. The residue was purified bya silica gel flash column with Hex/EA=5:1 to yield the titled compound(700 mg, 53%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=5.07 (d, J=8.8 Hz, 1H), 4.16-4.11 (m, 3H), 3.62 (t, J=6.2 Hz,2H), 2.32 (br. s., 1H), 2.12-2.04 (m, 1H), 1.75-1.68 (m, 2H), 1.62-1.56(m, 2H), 1.40 (s, 9H), 0.92 (d, J=7.2 Hz, 3H), 0.85 (d, J=7.2 Hz, 3H).

Intermediate Compound 58″:(S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (500mg, 1.73 mmol) and Celite® (diatomaceous earth, 2 g) in acetone (10 mL)at 0° C. The reaction proceeded at 0° C. for over 1 h and the reactionprogress was monitored by TLC. After completion, the reaction wasquenched with drops of iPrOH, diluted with EA (10 mL) and then filtered.The filtered cake was washed with EA (5 mL) and the combined filtratewas washed with saturated brine (2 mL×2), dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel flash columnwith Hex/EA=10:1-5:1 to yield the titled compound (170 mg, 32%) as awhite solid. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.03 (d,J=9.2 Hz, 1H), 4.30-4.24 (m, 1H), 4.22-4.13 (m, 2H), 2.46 (t, J=7.4 Hz,2H), 2.16-2.08 (m, 1H), 2.06-1.96 (m, 2H), 1.45 (s, 9H), 0.96 (d, J=6.8Hz, 3H), 0.89 (d, J=6.4 Hz, 3H).

Compound 58: (S)-4-(2-amino-3-methylbutanoyloxy)butanoic acid

A solution of(S)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid(104 mg, 0.34 mmol) in HCl/EA (˜2 M, 1.5 mL) stirred at 25° C. for 24 h.After that, the reaction mixture was filtered and the resultingprecipitate was collected, washed with Et₂O (0.5 mL), dried in vacuo toyield the titled compound (50 mg, 71%) as a white solid in HCl saltform. ¹H NMR was performed at 400 MHz with CD₃OD as solvent tocharacterize the titled compound, results are as follows: δ=4.33-4.26(m, 2H), 3.92 (d, J=4.8 Hz, 1H), 2.42 (t, J=7.2 Hz, 2H), 2.34-2.25 (m,1H), 2.05-1.94 (m, 2H), 1.06 (d, J=6.8 Hz, 6H).

A suspension of the above white solid (800 mg, 3.3 mmol) in ethanol (4mL) was stirred at 80° C. for around 30 min and a clear solution wasformed. Then the solution was gradually cooled to 25° C., propyleneoxide (580 mg, 10 mmol) was added dropwise. The reaction was stirred at25° C. for 16 h and then the resultant suspension was filtered. Thewhite solid was collected, washed with cold ethanol, dried in vacuo toafford the titled compound (510 mg, 75%) in free salt form. ¹H NMR wasperformed at 400 MHz with d₆-DMSO as solvent to characterize the titledcompound, results are as follows: δ=4.10-3.99 (m, 2H), 3.11 (d, J=5.2Hz, 1H), 2.29 (t, J=7.4 Hz, 2H), 1.90-1.74 (m, 3H), 0.87 (d, J=6.8 Hz,3H), 0.82 (d, J=6.4 Hz, 3H).

Example 1-59 Intermediate Compound 59′: 4-hydroxybutyl2-(p-tolyl)acetate

2-(p-tolyl)acetic acid (1 g, 6.67 mmol), DCC (1.5 g, 7.33 mmol) and DMAP(10 mg) was added to a stirred solution of butane-1,4-diol (3 g, 33.33mmol) in DCM (50 mL). The reaction was stirred at 25° C. for 16 h. Afterthat, the reaction mixture was filtered and the filtrate was washed withsaturated aqueous NH₄Cl (20 mL). The resultant organic phase was washedwith brine (20 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=3:1 to afford thetitled compound (1.1 g, 74%) as a colorless oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.18-7.12 (m, 4H), 4.12 (t, J=6.6 Hz, 2H),3.64 (t, J=6.4 Hz, 2H), 3.58 (s, 2H), 2.33 (s, 3H), 1.75-1.68 (m, 2H),1.62-1.55 (m, 2H).

Compound 59: 4-(2-(p-tolyl)acetoxy)butanoic acid

Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl2-(p-tolyl)acetate (800 mg, 3.60 mmol) and Celite® (diatomaceous earth,1.6 g) in acetone (15 mL) at 0° C. The reaction proceeded at 0° C. over1 h and the reaction progress was monitored by TLC. After completion,the reaction was quenched with drops of isopropanol, diluted with EA (30mL), and then filtered. The filtered cake was washed with EA (10 mL) andthe combined filtrate was washed with brine (10 mL×2), dried over Na₂SO₄and concentrated. The residue was purified by a silica gel flash columnwith Hex/EA=2:1 to afford the titled compound (500 mg, 59%) ascrystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=7.17-7.12 (m, 4H), 4.14 (t, J=6.2 Hz, 2H), 3.57 (s, 2H), 2.41 (t,J=7.2 Hz, 2H), 2.33 (s, 3H), 1.99-1.93 (m, 2H).

Example 1-60 Intermediate Compound 60′: (R)-4-hydroxybutyl2-(tert-butoxycarbonylamino)-3-methylbutanoate

DCC (3.1 g, 15.21 mmol) and DMAP (17 mg, 0.14 mmol) was added to astirred suspension of (R)-2-(tert-butoxycarbonylamino)-3-methylbutanoicacid (3.0 g, 13.82 mmol) and butane-1,4-diol (3.7 g, 41.47 mmol) in DCM(40 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 25° C. for 16 h. After that, the reaction mixture wasfiltered and the filtered cake was washed with DCM (10 mL). The combinedfiltrate was washed with saturated aqueous NH₄Cl (10 mL×2), dried overNa₂SO₄ and evaporated. The residue was purified by a silica gel flashcolumn with DCM/EA=20:1 to afford the titled compound (2.5 g, 63%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.02 (d,J=8.4 Hz, 1H), 4.20-4.16 (m, 2H), 3.68 (q, J=6.0 Hz, 2H), 2.16-2.08 (m,1H), 1.79-1.70 (m, 2H), 1.69-1.64 (m, 2H), 1.44 (s, 9H), 0.96 (d, J=6.8Hz, 3H), 0.89 (d, J=6.8 Hz, 3H).

Intermediate Compound 60″:(R)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid

Jones reagent was dropwise added to a stirred mixture of(R)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (2.5g, 8.65 mmol) and Celite® (diatomaceous earth, 5.0 g) in acetone (25 mL)at 0° C. The reaction proceeded at 0° C. over 1 h and the reactionprogress was monitored by TLC. After completion, the reaction wasquenched with drops of isopropanol, diluted with EA (25 mL), and thenfiltered. The filtered cake was washed with EA (25 mL) and the combinedfiltrate was washed with brine (20 mL×2), dried over Na₂SO₄ andconcentrated. The residue was purified by a silica gel flash column withDCM/EA=20:1-3:1 to afford the titled compound (1.1 g, 42%) as a whitesolid. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.03 (d,J=8.8 Hz, 1H), 4.26-4.18 (m, 2H), 2.45 (t, J=7.4 Hz, 2H), 2.14-2.10 (m,1H), 2.03-2.00 (m, 2H), 1.45 (s, 9H), 0.96 (d, J=6.8 Hz, 3H), 0.89 (d,J=6.8 Hz, 3H).

Compound 60: (R)-4-(2-amino-3-methylbutanoyloxy)butanoic acid

(R)-4-(2-(tert-butoxycarbonylamino)-3-methylbutanoyloxy)butanoic acid(400.0 mg, 1.32 mmol) was added to a stirred solution of HCl/EA (˜2 M, 2mL) at 0° C. The reaction was allowed to warm up gradually and stirredat 25° C. for 16 h. After that, the resulting suspension was filtered.The white precipitate was collected, washed with EA (2 mL) and dried invacuo to afford the titled compound (184.0 mg, 58%) as a white solid inHCl salt form. ¹H NMR was performed at 400 MHz with D₂O as solvent tocharacterize the titled compound, results are as follows: δ=4.32 (t,J=5.6 Hz, 2H), 4.03 (d, J=4.4 Hz, 1H), 2.51 (t, J=7.2 Hz, 2H), 2.39-2.35(m, 1H), 2.03 (t, J=6.6 Hz, 2H), 1.04 (t, J=7.2 Hz, 6H).

Example 1-61 Intermediate Compound 61′: (S)-4-hydroxybutyl2-(tert-butoxycarbonylamino)propanoate

A solution of (Boc)₂O (13.5 g, 61.80 mmol) in 1,4-dioxane (56 mL) wasadded to a stirred solution (S)-2-aminopropanoic acid (5.0 g, 56.18mmol) in water (56 mL) and aqueous NaOH (56.2 mL, 1 M) at 0° C. Thereaction was allowed to warm up gradually and stirred at 25° C. for 16h. After that, the reaction mixture was cooled to 0° C., then acidifiedwith HCl (2 M) until pH=2-3. The mixture was diluted with EA (56 mL),the aqueous phase was separated and extracted with EA (56 mL×3). Thecombined organic phase was washed with brine (56 mL), dried over Na₂SO₄and evaporated to afford the crude(S)-2-(tert-butoxycarbonylamino)propanoic acid (9.0 g) as a white solid,which was used directly for the next step without further purification.

DCC (4.4 g, 21.16 mmol) and DMAP (25 mg) was added to a stirredsuspension of the above crude (S)-2-(tert-butoxycarbonylamino)propanoicacid (4.0 g) and butane-1,4-diol (5.7 g, 63.49 mmol) in DCM (50 mL) at0° C. The reaction was allowed to warm up gradually and stirred at 25°C. for 16 h. After that, the reaction mixture was filtered, the filteredcake was washed with DCM (10 mL). The combined filtrate was washed withsaturated aqueous NH₄Cl (15 mL×2), dried over Na₂SO₄ and evaporated. Theresidue was purified by a silica gel flash column with PE/EA=4:1-1:1 toafford the titled compound (3.0 g, 55%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=5.02 (br. s., 1H), 4.29 (t, J=6.8Hz, 1H), 4.18 (t, J=6.4 Hz, 2H), 3.68 (q, J=6.0 Hz, 2H), 1.79-1.72 (m,2H), 1.68-1.60 (m, 2H), 1.44 (s, 9H), 1.38 (d, J=7.2 Hz, 3H).

Intermediate Compound 61″:(S)-4-(2-(tert-butoxycarbonylamino)propanoyloxy)butanoic acid

Jones reagent was dropwise added to a stirred mixture of(S)-4-hydroxybutyl 2-(tert-butoxycarbonylamino)propanoate (3.0 g, 11.49mmol) and Celite® (diatomaceous earth, 6.0 g) in acetone (30 mL) at 0°C. The reaction proceeded at 0° C. over 1 h and the reaction progresswas monitored by TLC. After completion, the reaction was quenched withdrops of isopropanol, diluted with EA (100 mL), and then filtered. Thefiltered cake was washed with EA (20 mL) and the combined filtrate waswashed with brine (30 mL×2), dried over Na₂SO₄ and concentrated. Theresidue was purified by a silica gel flash column with DCM/EA=20:1 toafford the titled compound (1.8 g, 57%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=5.06 (br. s., 1H), 4.31-4.16 (m,3H), 2.45 (t, J=7.2 Hz, 2H), 2.02-1.97 (m, 2H), 1.44 (s, 9H), 1.38 (d,J=7.2 Hz, 3H).

Compound 61: (S)-4-(2-aminopropanoyloxy)butanoic acid

(S)-4-(2-(tert-butoxycarbonylamino)propanoyloxy)butanoic acid (200.0 mg,0.73 mmol) was added to a stirred solution of HCl/EA (1.0 mL, ˜2 M) at0° C. The reaction was allowed to warm up gradually and stirred at 25°C. for 16 h. After that, the reaction mixture was evaporated, theresidue was purified by prep-HPLC to afford the titled compound (80.0mg, 52%) as a colorless oil in HCl salt form. ¹H NMR was performed at400 MHz with CD₃OD as solvent to characterize the titled compound,results are as follows: δ=4.31-4.27 (m, 2H), 4.11 (q, J=7.2 Hz, 1H),2.48-2.41 (m, 2H), 2.04-1.97 (m, 2H), 1.55 (dd, J=1.6, 7.2 Hz, 3H).

Example 1-62 Intermediate Compound 62′: (S)-4-hydroxybutyl2-acetamidopropanoate

Ac₂O (6.8 g, 66.67 mmol) was added to a stirred suspension of(S)-2-aminopropanoic acid (5.0 g, 56.18 mmol) in HOAc (25 mL). Thereaction was stirred at 25° C. for 16 h. After that, the reactionmixture was evaporated to yield the crude (S)-2-acetamidopropanoic acidas a white solid (8.0 g), which was used directly for next step withoutfurther purification.

DCC (3.1 g, 15.28 mmol) and DMAP (20 mg) was added to a stirredsuspension of the above (S)-2-acetamidopropanoic acid (2.0 g, 15.28mmol) and butane-1,4-diol (4.1 g, 45.80 mmol) in DCM (50 mL). Thereaction was stirred at 25° C. for 16 h. After that, the reactionmixture was filtered and the filtrate was concentrated. The residue waspurified by prep-HPLC to afford the titled compound (2.0 g, 67%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=6.12 (br.s., 1H), 4.59-4.52 (m, 1H), 4.24-4.13 (m, 2H), 3.67 (t, J=6.4 Hz, 2H),2.01 (s, 3H), 1.77-1.72 (m, 2H), 1.66-1.59 (m, 2H), 1.40 (d, J=7.6 Hz,3H).

Compound 62: (S)-4-(2-acetamidopropanoyloxy)butanoic acid

Jones reagent was dropwise added to a stirred mixture of(S)-4-hydroxybutyl 2-acetamidopropanoate (660 mg, 3.25 mmol) and Celite®(diatomaceous earth, 1.2 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops ofisopropanol, diluted with EA (10 mL), and then filtered. The filteredcake was washed with EA (10 mL) and the combined filtrate was washedwith brine (10 mL×2), dried over Na₂SO₄ and concentrated. The residuewas purified by prep-HPLC to afford the titled compound (300 mg, 42%) asa colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solventto characterize the titled compound, results are as follows: δ=6.25 (d,J=6.4 Hz, 1H), 4.61-4.54 (m, 1H), 4.28-4.15 (m, 2H), 2.44 (t, J=7.0 Hz,2H), 2.03 (s, 3H), 2.07-1.97 (m, 2H), 1.40 (d, J=7.2 Hz, 3H).

Example 1-63 Intermediate Compound 63′: benzyl4-(2-(tert-butoxycarbonyl)aminoacetoxy)butanoate

A mixture of N-Boc glycine (2.0 g, 11.4 mmol), benzyl 4-hydroxybutanoate(2.7 g, 13.7 mmol), DCC (3.1 g, 14.8 mmol) and DMAP (5 mg) in DCM (20mL) was stirred at 25° C. for 16 h. The reaction mixture was filteredand the filtrate was washed with aqueous saturated NH₄Cl (2×20 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by a silica gel flash column with PE/EA=10:1-1:1 toafford the titled compound (2.0 g, 50%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.45-7.27 (m, 5H), 5.13 (s, 2H),4.99 (br. s., 1H), 4.20 (t, J=6.2 Hz, 2H), 3.88 (d, J=4.4 Hz, 2H), 2.46(t, J=7.4 Hz, 2H), 2.04-1.97 (m, 2H), 1.45 (s, 9H).

Intermediate Compound 63″: benzyl 4-(2-aminoacetoxy)butanoate

TFA (3.0 mL) was added to a solution of benzyl4-(2-(tert-butoxycarbonyl)aminoacetoxy)butanoate (1.60 g, 4.56 mmol) inDCM (15 mL) at 0° C., and the reaction was stirred at the sametemperature for 2 h. After that, solvent was evaporated to afford thetitled compound (1.2 g), which was used directly for the next stepwithout further purification.

Intermediate Compound 63′″: benzyl 4-(2-propionamidoacetoxy)butanoate

Propionyl chloride (162 mg, 1.75 mmol) was dropwise added to a solutionof benzyl 4-(2-aminoacetoxy)butanoate (400 mg, 1.59 mmol) and Et₃N (0.66mL, 4.78 mmol) in DCM (10 mL) at 0° C. The reaction was allowed to warmup and stirred at 25° C. for 16 h. After that, the reaction was quenchedby water (10 mL) with stirring for 5 min. The aqueous phase wasextracted with DCM (10 mL×3), the combined organic phase was washed withbrine (20 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel flash column with PE/EA=1:1 to afford the titledcompound (440 mg, 90%) as colorless oil.

Compound 63: 4-(2-propionamidoacetoxy)butanoic acid

Pd/C (50 mg) was added to a solution of benzyl4-(2-propionamidoacetoxy)butanoate (400 mg, 1.3 mmol) in MeOH (10 mL),and the mixture was stirred at 25° C. for 16 h under H₂ atmosphere.After that, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by a silica gel flash column withPE/EA=1:50 to afford the titled compound (170 mg, 60%) as a white solid.¹H NMR was performed at 400 MHz with CD₃OD as solvent to characterizethe titled compound, results are as follows: δ=4.18 (t, J=6.2 Hz, 2H),3.92 (s, 2H), 2.39 (t, J=7.4 Hz, 2H), 2.27 (q, J=7.6 Hz, 2H), 1.98-1.91(m, 2H), 1.14 (t, J=7.6 Hz, 3H).

Example 1-64 Intermediate Compound 64′: benzyl4-(2-isobutyramidoacetoxy)butanoate

Isobutyryl chloride (0.8 g, 7.5 mmol) was added dropwise to a solutionof benzyl 4-(2-aminoacetoxy)butanoate (1.57 g, 6.26 mmol) and Et₃N (1.58mL, 15.7 mmol) in DCM (20 mL) at 0° C. The reaction was stirred at 25°C. for 16 h and then washed with brine (2×10 mL). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby prep-HPLC to afford the titled compound (0.8 g, 40%) as a colorlessoil. ¹H NMR was performed at 600 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.45-7.27(m, 5H), 5.93 (br. s., 1H), 5.12 (s, 2H), 4.20 (t, J=6.3 Hz, 2H), 4.00(d, J=4.8 Hz, 2H), 2.50-2.37 (m, 3H), 2.04-1.99 (m, 2H), 1.18 (d, J=7.2Hz, 6H).

Compound 64: 4-(2-isobutyramidoacetoxy)butanoic acid

Pd/C (75 mg) was added to a solution of benzyl4-(2-isobutyramidoacetoxy)butanoate (0.75 g, 2.3 mmol) in EA (10 mL).The reaction was stirred under H₂ atmosphere for 16 h at 25° C. Thereaction was filtered and the filtrate was concentrated. The residue waspurified by a silica gel flash column with PE/EA=5:1-3:1 to afford thetitled compound (270 mg, 50%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=6.04 (br. s., 1H), 4.24 (t, J=6.2 Hz, 2H),4.03 (d, J=5.2 Hz, 2H), 2.57-2.36 (m, 3H), 2.06-1.99 (m, 2H), 1.18 (d,J=7.2 Hz, 6H).

Example 1-65 Intermediate Compound 65′: benzyl4-(2-(tert-butoxycarbonyl)methylaminoacetoxy)butanoate

A mixture of 2-((tert-butoxycarbonyl)methylamino)acetic acid (5.0 g,26.45 mmol), benzyl 4-hydroxybutanoate (4.6 g, 23.71 mmol), DCC (6.0 g,29.07 mmol) and DMAP (cat.) in DCM (100 mL) was stirred at 25° C. for 16h. After that, the reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by a silica gel flash column withPE/EA=10:1 to afford the titled compound (8.0 g, 83%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.35-7.26(m, 5H), 5.12 (s, 2H), 4.17 (q, J=5.6 Hz, 2H), 3.94 (s, 1H), 3.86 (s,1H), 2.90 (d, J=6.8 Hz, 3H), 2.45 (t, J=7.4 Hz, 2H), 2.02-1.97 (m, 2H),1.43 (d, J=19.6 Hz, 9H).

Intermediate Compound 65″: benzyl4-(2-(N-methylacetamido)acetoxy)butanoate

TFA (8.0 mL) was added to a solution of benzyl4-(2-(tert-butoxycarbonyl)methylaminoacetoxy)butanoate (8.0 g, 21.89mmol) in DCM (80 mL) at 0° C., the reaction was stirred at the sametemperature for 2 h. After that, solvent was evaporated, the residue(5.8 g) was used directly for next step.

The above residue (5.8 g) was dissolved in DCM (60 mL), to which Et₃N(9.2 mL, 65.58 mmol) was added, followed by addition of acetyl chloride(3.4 g, 43.72 mmol) at 0° C. The reaction was allowed to warm up andstirred at 25° C. for 16 h. After that, solvent was evaporated, and theresidue was purified by prep-HPLC to afford the titled compound (4.0 g,59%) as a colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=7.35-7.31 (m, 5H), 5.10 (s, 2H), 4.14 (t, J=6.2 Hz, 2H), 4.06 (s, 2H),3.03 (s, 3H), 2.43 (t, J=7.4 Hz, 2H), 2.10 (s, 2H), 2.11-1.96 (m, 3H).

Compound 65: 4-(2-(N-methylacetamido)acetoxy)butanoic acid

Pd/C (400 mg) was added to a solution of benzyl4-(2-(N-methylacetamido)acetoxy)butanoate (4.0 g, 13.01 mmol) in MeOH(40 mL), and the reaction was stirred at 25° C. for 16 h under H₂atmosphere. After that, the reaction mixture was filtered. The filtratewas concentrated and the residue was purified by a silica gel flashcolumn with PE/EA=1:10 to afford the titled compound (1.2 g, 42%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.92 (br.s., 1H), 4.20 (t, J=6.2 Hz, 2H), 4.11 (s, 2H), 3.09 (s, 3H), 2.42 (t,J=7.2 Hz, 2H), 2.16 (s, 3H), 2.02-1.95 (m, 2H).

Example 1-66 Intermediate Compound 66′: benzyl4-(2-acetamidoacetoxy)butanoate

2-acetamidoacetic acid (362 mg, 3.09 mmol), DCC (584 mg, 2.83 mmol) andDMAP (5 mg) was added to a stirred solution of benzyl 4-hydroxybutanoate(500 mg, 2.58 mmol) in DCM (20 mL). The reaction was stirred at 25° C.for 16 h. After that, the reaction mixture was filtered. The filtratewas washed with saturated aqueous NH₄Cl (15 mL), the organic phase wasseparated, washed with brine (10 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by prep-HPLC to afford the titledcompound (320 mg, 42%) as crystalline solids. ¹H NMR was performed at400 MHz with CD₃OD as solvent to characterize the titled compound,results are as follows: δ=7.36-7.31 (m, 5H), 5.13 (s, 2H), 4.17 (t,J=6.2 Hz, 2H), 3.88 (s, 2H), 2.48 (t, J=7.4H, 2H), 2.01-1.94 (m, 5H).

Compound 66: 4-(2-acetamidoacetoxy)butanoic acid

Pd/C (30 mg) was added to a solution of benzyl4-(2-acetamidoacetoxy)butanoate (280 mg, 0.96 mmol) in methanol (10 mL),the reaction was stirred at 25° C. under H₂ atmosphere for 16 h. Aftercompletion, the reaction mixture was filtered through Celite®(diatomaceous earth) and the filtrate was concentrated. The residue waspurified by prep-HPLC to afford the titled compound (110 mg, 57%) ascrystalline solids. ¹H NMR was performed at 400 MHz with CD₃OD assolvent to characterize the titled compound, results are as follows:δ=4.18 (t, J=6.4 Hz, 2H), 3.92 (s, 2H), 2.39 (t, J=7.4 Hz, 2H), 2.00 (s,3H), 1.98-1.91 (m, 2H).

Example 1-67

Intermediate Compound 67′: (S)-4-hydroxybutyl2-acetamido-3-methylbutanoate

HATU (5258 mg, 13.84 mmol) and DIPEA (3245 mg, 25.16 mmol) was added toa stirred solution of (S)-2-acetamido-3-methylbutanoic acid (2 g, 12.58mmol) and butane-1,4-diol (3396 mg, 37.74 mmol) in DCM (50 mL). Thereaction was stirred at 25° C. for 16 h. After that, the mixture wasconcentrated and the residue was purified by prep-HPLC to afford thetitled compound (600 mg, 21%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=5.96 (d, J=8.0 Hz, 1H), 4.54 (dd, J=5.0, 8.6Hz, 1H), 4.26-4.11 (m, 2H), 3.69 (t, J=6.4 Hz, 2H), 2.18-2.11 (m, 1H),2.05 (s, 3H), 1.79-1.72 (m, 2H), 1.69-1.65 (m, 2H), 0.95 (d, J=6.8 Hz,3H), 0.91 (d, J=6.8 Hz, 3H).

Compound 67: (S)-4-(2-acetamido-3-methylbutanoyloxy)butanoic acid

Jones reagent was added dropwise to a stirred mixture of(S)-4-hydroxybutyl 2-acetamido-3-methylbutanoate (500 mg, 2.16 mmol) andCelite® (diatomaceous earth, 1 g) in acetone (10 mL) at 0° C. Thereaction proceeded at 0° C. over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction mixture was quenched bydrops of isopropanol, diluted with EA (10 mL) and then filtered. Thefiltered cake was washed with EA (10 mL), the combined filtrate waswashed with brine (5 mL×2), dried over Na₂SO₄ and concentrated. Theresidue was purified by prep-HPLC to afford the titled compound (190 mg,36%) as crystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃as solvent to characterize the titled compound, results are as follows:δ=6.18 (d, J=7.2 Hz, 1H), 4.55 (dd, J=4.8, 8.4 Hz, 1H), 4.30-4.24 (m,1H), 4.20-4.14 (m, 1H), 2.47 (t, J=7.0 Hz, 2H), 2.20-2.12 (m, 1H), 2.09(s, 3H), 2.06-1.98 (m, 2H), 0.95 (d, J=6.8 Hz, 3H), 0.91 (d, J=6.8 Hz,3H).

Example 1-68 Intermediate Compound 68′: 2-(ethoxycarbonylamino)aceticacid

Ethyl carbonochloridate (3.8 g, 34.6 mmol) was dropwise added tosolution of glycine (2.0 g, 26.6 mmol) and K₂CO₃ (9.6 g, 96.3 mmol) inwater (40 mL) at 0° C. The reaction was warmed up to 25° C. and stirredfor 16 h. After that, the reaction mixture was extracted with EA (2×20mL). The aqueous phase was separated and acidified with cold conc. HCluntil pH=2, which was extracted with EA (2×40 mL). The combined organiclayer was dried over Na₂SO₄, filtered and concentrated to afford thetitled compound (3.5 g, 89%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=5.16 (br. s., 1H), 4.24-4.08 (m, 2H),4.07-3.93 (m, 2H), 1.41-1.14 (m, 3H).

Intermediate Compound 68″: 4-hydroxybutyl 2-(ethoxycarbonylamino)acetate

A mixture of 2-(ethoxycarbonylamino)acetic acid (1.0 g, 6.8 mmol),butane-1,4-diol (3.1 g, 34.0 mmol), DCC (1.7 g, 8.2 mmol) and DMAP (10mg) in DCM (30 mL) was stirred at 25° C. for 16 h. After that, thereaction mixture was filtered and the filtrate was washed with water(2×20 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified by a silica gel flash columnwith PE/EA=5:1-2:1 to afford the titled compound (630 mg, 42%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.16 (br.s., 1H), 4.20 (t, J=6.6 Hz, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.95 (d, J=5.2Hz, 2H), 3.68 (t, J=6.2 Hz, 2H), 1.83-1.69 (m, 2H), 1.69-1.52 (m, 2H),1.25 (t, J=7.2 Hz, 3H).

Compound 68: 4-(2-(ethoxycarbonyl)aminoacetoxy)butanoic acid

Jones reagent was added in portions to a mixture of 4-hydroxybutyl2-(ethoxycarbonylamino)acetate (500 mg, 2.3 mmol) and Celite®(diatomaceous earth, 1.5 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 30 min and the reaction progress was monitoredby TLC. After completion, the reaction mixture was quenched by drops ofisopropanol, diluted with EA (20 mL) and filtered. The filtered cake waswashed with EA (10 mL), the combined filtrate was washed with brine (5mL×2), dried over Na₂SO₄ and concentrated. The residue was purified by asilica gel flash column with DCM/EA=20:1-5:1 to afford the titledcompound (190 mg, 36%) as a white solid. ¹H NMR was performed at 400 MHzwith CDCl₃ as solvent to characterize the titled compound, results areas follows: δ=5.20 (br. s., 1H), 4.23 (t, J=6.4 Hz, 2H), 4.14 (q, J=7.2Hz, 2H), 3.96 (d, J=5.6 Hz, 2H), 2.46 (t, J=7.2 Hz, 2H), 2.04-1.97 (m,2H), 1.25 (t, J=7.0 Hz, 3H).

Example 1-69 Intermediate Compound 69′:2-(isopropoxycarbonylamino)acetic acid

Isopropyl carbonochloridate (2.1 g, 17.3 mmol) was dropwise added tosolution of glycine (1.0 g, 13.3 mmol) and K₂CO₃ (4.8 g, 34.6 mmol) inwater (30 mL) at 0° C. The reaction was warmed up to 25° C. and stirredfor 16 h. After that, the reaction mixture was extracted with EA (2×20mL). The aqueous phase was separated and acidified with cold conc. HCluntil pH=2, which was extracted with EA (2×30 mL). The combined organiclayer was dried over Na₂SO₄, filtered and concentrated to afford thetitled compound (2.0 g, 93%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=5.21 (br. s., 1H), 4.98-4.89 (m, 1H),4.02-3.96 (m, 2H), 1.26-1.23 (m, 6H).

Intermediate Compound 69″: 4-hydroxybutyl2-(isopropoxycarbonylamino)acetate

A mixture of 2-(isopropoxycarbonylamino)acetic acid (500 mg, 3.1 mmol),butane-1,4-diol (839 mg, 9.3 mmol), DCC (768 mg, 3.7 mmol) and DMAP (10mg) in DCM (10 mL) was stirred at 25° C. for 16 h. After that, thereaction mixture was filtered and the filtrate was washed with water(2×20 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified by a silica gel flash columnwith PE/EA=10:1-1:1 to afford the titled compound (500 mg, 69%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.10 (br.s., 1H), 4.95-4.88 (m, 1H), 4.20 (t, J=6.4 Hz, 2H), 3.95 (d, J=5.6 Hz,2H), 3.68 (t, J=6.2 Hz, 2H), 1.79-1.72 (m, 2H), 1.67-1.57 (m, 2H), 1.24(d, J=6.4 Hz, 6H).

Compound 69: 4-(2-(isopropoxycarbonyl)aminoacetoxy)butanoic acid

Jones reagent was added in portions to a mixture of 4-hydroxybutyl2-(isopropoxycarbonylamino)acetate (500 mg, 2.1 mmol) and Celite®(diatomaceous earth, 1.5 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 30 min and the reaction progress was monitoredby TLC. After completion, the reaction mixture was quenched by drops ofisopropanol, diluted with EA (20 mL) and filtered. The filtered cake waswashed with EA (10 mL), the combined filtrate was washed with brine (5mL×2), dried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC to afford the titled compound (220 mg, 42%) as a white solid.¹H NMR was performed at 400 MHz with CDCl₃ as solvent to characterizethe titled compound, results are as follows: δ=5.13 (br. s., 1H),4.95-4.89 (m, 1H), 4.22 (t, J=6.2 Hz, 2H), 3.95 (d, J=5.6 Hz, 2H), 2.46(t, J=7.2 Hz, 2H), 2.04-1.97 (m, 2H), 1.24 (d, J=6.4 Hz, 6H).

Example 1-70 Intermediate Compound 70′:2-((cyclohexyloxy)carbonylamino)acetic acid

Pyridine (1.2 g, 15.0 mmol) was added dropwise to a solution oftriphosgene (3.6 g, 12.0 mmol) in toluene (20 mL) at 0° C., and theformed yellow slurry was stirred for 0.5 h. After that, a solution ofcyclohexanol (1.0 g, 10.0 mmol) in toluene (10 mL) was added dropwise at0° C. The reaction was allowed to warm up and stirred at 25° C. foradditional 1 h, then was quenched by the addition of water (30 mL). Theresulting aqueous phase was extracted with EA (2×20 mL). The combinedorganic layer was dried over MgSO₄, filtered and concentrated. Theresidue was used directly for the next step without purification.

The above crude cyclohexyl carbonochloridate was added dropwise tosolution of glycine (675 mg, 9.0 mmol) and K₂CO₃ (3.5 g, 25.0 mmol) inwater (20 mL) at 0° C. The reaction was allowed to warm up and stirredat 25° C. for 16 h. After that, the reaction mixture was extracted withEA (2×30 mL). The aqueous phase was separated and acidified with coldconc. HCl until pH=2, which was extracted with EA (2×30 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedto afford the titled compound (0.9 g, 45%) as a white solid. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=5.14 (br. s., 1H), 4.79-4.59 (m,1H), 4.07-3.92 (m, 2H), 1.95-1.80 (m, 2H), 1.73-1.70 (m, 2H), 1.61-1.14(m, 6H).

Intermediate Compound 70″: benzyl4-(2-((cyclohexyloxy)carbonylamino)acetoxy)butanoate

A solution of 2-((cyclohexyloxy)carbonylamino)acetic acid (850 mg, 4.2mmol), benzyl 4-hydroxybutanoate (985 mg, 6.3 mmol), HATU (1.9 g, 5.1mmol) and DIPEA (819 mg, 6.3 mmol) in DCM (20 mL) was stirred at 25° C.for 16 h. After that, the reaction mixture was diluted with DCM (10 mL)and washed with water (2×20 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated. The residue was purified by asilica gel column with PE/EA=100:1-5:1 to afford the titled compound(0.9 g, 56%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=7.42-7.29 (m, 5H), 5.12 (s, 2H), 5.08 (br. s., 1H), 4.77-4.55(m, 1H), 4.20 (t, J=6.4 Hz, 2H), 3.93 (d, J=5.6 Hz, 2H), 2.45 (t, J=7.6Hz, 2H), 2.04-1.97 (m, 2H), 1.87-1.85 (m, 2H), 1.78-1.64 (m, 2H),1.58-1.46 (m, 1H), 1.46-1.14 (m, 5H).

Compound 70: 4-(2-(cyclohexyloxy)carbonylaminoacetoxy)butanoic acid

Pd/C (90 mg) was added to a solution of benzyl4-(2-((cyclohexyloxy)carbonylamino)acetoxy)butanoate (900 mg, 2.4 mmol)in EA (10 mL). The reaction was stirred under H₂ atmosphere at 25° C.for 16 h. After that, the reaction mixture was filtered and the filtratewas concentrated. The residue was purified by a silica gel flash columnwith PE/EA=10:1-1:1 to afford the titled compound (220 mg, 32%) as awhite solid. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.13 (br.s., 1H), 4.67-4.62 (m, 1H), 4.23 (t, J=6.2 Hz, 2H), 3.95 (d, J=6.0 Hz,2H), 2.46 (t, J=7.2 Hz, 2H), 2.05-1.98 (m, 2H), 1.88-1.86 (m, 2H),1.72-1.70 (m, 2H), 1.59-1.47 (m, 1H), 1.46-1.12 (m, 5H).

Example 1-71 Intermediate Compound 71′:(S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid

Ethyl carbonochloridate (1.9 g, 17.3 mmol) was added dropwise to asolution of L-valine (1.0 g, 8.5 mmol) and K₂CO₃ (4.8 g, 34.6 mmol) inwater (30 mL) at 0° C. The reaction was allowed to warm up and stirredat 25° C. for 16 h. After that, the reaction mixture was extracted withEA (2×20 mL). The aqueous phase was separated and acidified with coldconc. HCl until pH=2, which was extracted with EA (2×30 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedto afford the titled compound (1.5 g, 60%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=5.12 (d, J=9.2 Hz, 1H), 4.33(dd, J=4.6, 9.0 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 2.32-2.11 (m, 1H), 1.26(t, J=7.2 Hz, 3H), 1.01 (d, J=6.4 Hz, 3H), 0.94 (d, J=7.2 Hz, 3H).

Intermediate Compound 71″: (S)-4-(benzyloxy)-4-oxobutyl2-(ethoxycarbonylamino)-3-methylbutanoate

A solution of (S)-2-(ethoxycarbonylamino)-3-methylbutanoic acid (536 mg,2.8 mmol), benzyl 4-hydroxybutanoate (500 mg, 2.6 mmol), HATU (1.2 g,3.1 mmol) and DIPEA (499 mg, 3.9 mmol) in DCM (20 mL) was stirred at 25°C. for 16 h. After that, the reaction mixture was diluted with DCM (10mL) and washed with water (2×20 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel flash column with PE/EA=20:1-5:1 to afford the titled compound (370mg, 39%) as a colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃as solvent to characterize the titled compound, results are as follows:δ=7.45-7.46 (m, 5H), 5.13 (s, 2H), 4.26 (dd, J=4.8, 8.8 Hz, 1H), 4.17(t, J=6.4 Hz, 2H), 4.11 (q, J=7.2 Hz, 2H), 2.46 (t, J=7.6 Hz, 2H),2.21-2.07 (m, 1H), 2.04-1.97 (m, 2H), 1.24 (t, J=7.0 Hz, 3H), 0.96 (d,J=6.8 Hz, 3H), 0.87 (d, J=6.8 Hz, 3H).

Compound 71:(S)-4-(2-((ethoxycarbonyl)amino)-3-methylbutanoyloxy)butanoic acid

Pd/C (40 mg) was added to a solution of (S)-4-(benzyloxy)-4-oxobutyl2-(ethoxycarbonylamino)-3-methylbutanoate (350 mg, 1.0 mmol) in EA (10mL). The reaction was stirred under H₂ atmosphere at 25° C. for 16 h.The reaction was filtered and the filtrate was concentrated to affordthe titled compound (240 mg, 91%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=5.16 (d, J=8.8 Hz, 1H), 4.28-4.10(m, 5H), 2.46 (t, J=7.2 Hz, 2H), 2.25-2.08 (m, 1H), 2.05-1.96 (m, 2H),1.25 (t, J=7.0 Hz, 3H), 0.93 (dd, J=7.0, 31.4 Hz, 6H).

Example 1-72 Intermediate Compound 72′: benzyl 4-hydroxybutanoate

A mixture of dihydrofuran-2(3H)-one (5.1 g, 59.2 mmol) and NaOH (2.37 g,59.2 mmol) in H₂O (60 mL) was heated under 100° C. for 1 h. The clearsolution was then cooled and concentrated. The resultant solid wassuspended in toluene and concentrated to remove H₂O. The resultant solidwas suspended in acetone (60 mL), to which TBAF (772 mg, 2.96 mmol) and(bromomethyl)benzene (12.2 g, 71.1 mmol) was added. The reaction washeated under reflux for 3 h. After that, the reaction mixture waspartitioned between EA (150 mL) and H₂O (100 mL). The organic layer wasseparated, dried over Na₂SO₄ and concentrated. The residue was purifiedby a silica gel flash column with Hex/EA=2:1-1:2 to afford the titledcompound (8.5 g, 74%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=7.37-7.34 (m, 5H), 5.13 (s, 2H), 3.68 (t, J=6.2 Hz,2H), 2.50 (t, J=7.2 Hz, 2H), 1.94-1.87 (m, 2H).

Intermediate Compound 72″: (S)-4-(benzyloxy)-4-oxobutyl5-oxopyrrolidine-2-carboxylate

HATU (2.9 g, 7.7 mmol) and DIPEA (998 mg, 7.7 mmol) was added to asolution of L-pyroglutamic acid (731 mg, 5.7 mmol) and benzyl4-hydroxybutanoate (1.0 g, 5.1 mmol) in DMF (20 mL). The mixture wasstirred at 25° C. for 16 h. The reaction was concentrated and theresidue was purified by prep-HPLC to afford the titled compound (0.9 g,57%) as a colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=7.39-7.33 (m, 5H), 6.34 (br. s., 1H), 5.13 (s, 2H), 4.21 (t, J=6.0 Hz,3H), 2.53-2.28 (m, 5H), 2.27-2.13 (m, 1H), 2.09-1.96 (m, 2H).

Compound 72: (S)-4-(5-oxopyrrolidine-2-carbonyloxy)butanoic acid

Pd/C (90 mg) was added to a solution of (S)-4-(benzyloxy)-4-oxobutyl5-oxopyrrolidine-2-carboxylate (900 mg, 3.0 mmol) in EA (20 mL). Thereaction was stirred under H₂ atmosphere at 25° C. for 16 h. After that,the reaction mixture was filtered and the filtrate was concentrated toafford the titled compound (580 mg, 91%) as a white solid. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.98 (br. s., 1H), 4.31-4.16 (m,3H), 2.52-2.39 (m, 5H), 2.35-2.19 (m, 1H), 2.06-1.94 (m, 2H).

Example 1-73 Intermediate Compound 73′: 4-hydroxybutyl (2-methoxyphenyl)carbonate

A solution of 2-methoxyphenol (1 g, 8.06 mmol) and Et₃N (977 mg, 9.68mmol) in DCM (10 mL) was added dropwise to a stirred solution oftriphosgene (788 mg, 2.66 mmol) in DCM (10 mL) at 0° C. during 10 min.After that, the reaction was allowed to warm up gradually and stirred at25° C. for 2 h. The above reaction solution was added dropwise to astirred solution of butane-1,4-diol (2.18 g, 24.19 mmol) in DCM (10 mL)at 0° C. during 10 min, and then the reaction mixture was stirred at 25°C. for 14 h. After that, the reaction mixture was diluted with water (10mL), separated and the organic phase was washed with brine (10 mL),dried over Na₂SO₄ and concentrated. The residue was purified by a silicagel flash column with DCM/EA=10:1 to afford the titled compound (350 mg,27%) as a colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=7.22 (t, J=8.0 Hz, 1H), 7.13 (d, J=6.8 Hz, 1H), 6.99-6.93 (m, 2H),4.30 (t, J=6.4 Hz, 2H), 3.86 (s, 3H), 3.72 (t, J=6.2 Hz, 2H), 1.89-1.82(m, 2H), 1.75-1.68 (m, 2H).

Compound 73: 4-((2-methoxyphenoxy)carbonyloxy)butanoic acid

Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl(2-methoxyphenyl) carbonate (350 mg, 1.46 mmol) and Celite®(diatomaceous earth, 700 mg) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops ofisopropanol, diluted with EA (15 mL), and then filtered. The filteredcake was washed with EA (5 mL) and the combined filtrate was washed withbrine (5 mL×2), dried over Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with DCM/EA=10:1 to afford thetitled compound (180 mg, 49%) as crystalline solids. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.22 (t, J=8.0 Hz, 1H), 7.13 (d,J=6.8 Hz, 1H), 6.99-6.93 (m, 2H), 4.33 (t, J=6.2 Hz, 2H), 3.86 (s, 3H),2.55 (t, J=7.4 Hz, 2H), 2.12-2.05 (m, 2H).

Example 1-74 Intermediate Compound 74′: 4-hydroxybutyl(2-isopropyl-5-methylphenyl) carbonate

A solution of 2-isopropyl-5-methylphenol (1 g, 6.67 mmol) and Et₃N (741mg, 7.33 mmol) in DCM (10 mL) was added dropwise to a stirred solutionof triphosgene (651 mg, 2.20 mmol) in DCM (10 mL) at 0° C. during 10min. After that, the reaction was allowed to warm up gradually andstirred at 0-25° C. for 2 h. The above reaction solution was dropwiseadded to a stirred solution of butane-1,4-diol (1.8 g, 20 mmol) in DCM(10 mL) at 0° C. during 10 min, and then the reaction mixture wasstirred at 0-25° C. for 14 h. After that, the reaction mixture wasdiluted with water (10 mL), separated and the organic phase was washedwith brine (10 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=3:1 to afford thetitled compound (900 mg, 51%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.19 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.8 Hz,1H), 6.90 (s, 1H), 4.30 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.2 Hz, 2H),3.10-3.03 (m, 1H), 2.32 (s, 3H), 1.89-1.82 (m, 2H), 1.75-1.68 (m, 2H),1.20 (d, J=7.2 Hz, 6H).

Compound 74: 4-((2-isopropyl-5-methylphenoxy)carbonyloxy)butanoic acid

Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl(2-isopropyl-5-methylphenyl) carbonate (900 mg, 3.38 mmol) and Celite®(diatomaceous earth, 1.8 g) in acetone (10 mL) at 0° C. The reactionproceeded at 0° C. over 1 h and the reaction progress was monitored byTLC. After completion, the reaction was quenched with drops ofisopropanol, diluted with EA (30 mL), and then filtered. The filteredcake was washed with EA (10 mL) and the combined filtrate was washedwith brine (10 mL×2), dried over Na₂SO₄ and concentrated. The residuewas purified by a silica gel flash column with DCM/EA=8:1 to afford thetitled compound (500 mg, 53%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.19 (d, J=8.0 Hz, 1H), 7.04 (d, J=7.8 Hz,1H), 6.90 (s, 1H), 4.32 (t, J=6.2 Hz, 2H), 3.09-3.02 (m, 1H), 2.55 (t,J=7.2 Hz, 2H), 2.32 (s, 3H), 2.13-2.06 (m, 2H), 1.20 (d, J=6.8 Hz, 6H).

Example 1-75 Intermediate Compound 75′: benzo[d][1,3]dioxol-5-yl(4-hydroxybutyl) carbonate

A solution of benzo[d][1,3]dioxol-5-ol (1 g, 7.25 mmol) and Et₃N (878mg, 8.70 mmol) in DCM (10 mL) was added dropwise to a stirred solutionof triphosgene (708 mg, 2.39 mmol) in DCM (10 mL) at 0° C. during 10min. After that, the reaction was allowed to warm up gradually andstirred at 0-25° C. for 2 h. The above reaction solution was dropwiseadded to a stirred solution of butane-1,4-diol (1.96 g, 21.74 mmol) inDCM (10 mL) at 0° C. during 10 min, and then the reaction mixture wasstirred at 0-25° C. for 14 h. After that, the reaction mixture wasdiluted with water (10 mL), separated and the organic phase was washedwith brine (10 mL), dried over Na₂SO₄ and concentrated, the residue waspurified by a silica gel flash column with DCM/EA=10:1 to afford thetitled compound (500 mg, 27%) as a yellow oil. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=6.75 (d, J=8.4 Hz, 1H), 6.67 (d, J=2.0 Hz,1H), 6.60 (dd, J=2.0, 8.4 Hz, 1H), 5.97 (s, 2H), 4.26 (t, J=6.6 Hz, 2H),3.68 (t, J=6.2 Hz, 2H), 1.85-1.78 (m, 2H), 1.71-1.64 (m, 2H).

Compound 75: 4-((benzo[d][1,3]dioxol-5-yloxy)carbonyloxy)butanoic acid

Jones reagent was added dropwise to a stirred mixture ofbenzo[d][1,3]dioxol-5-yl (4-hydroxybutyl) carbonate (500 mg, 1.97 mmol)and Celite® (diatomaceous earth, 1 g) in acetone (10 mL) at 0° C. Thereaction proceeded at 0° C. over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof isopropanol, diluted with EA (30 mL), and then filtered. The filteredcake was washed with EA (10 mL) and the combined filtrate was washedwith brine (10 mL×2), dried over Na₂SO₄ and concentrated. The residuewas purified by a silica gel flash column with DCM/EA=8:1 to afford thetitled compound (300 mg, 57%) as brown solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=6.77 (d, J=8.4 Hz, 1H), 6.69 (d, J=1.6 Hz,1H), 6.62 (dd, J=2.0, 8.4 Hz, 1H), 5.99 (s, 2H), 4.30 (t, J=6.2 Hz, 2H),2.54 (t, J=7.2 Hz, 2H), 2.11-2.05 (m, 2H).

Example 1-76 Intermediate Compound 76′: 4-methylbenzyl carbonochloridate

Pyridine (4.86 g, 61.48 mmol) was added to a stirred solution oftriphosgene (14.5 g, 49.18 mmol) in toluene (100 mL) at 0° C. and themixture was stirred for 30 min. After that, a solution ofp-tolylmethanol (5 g, 40.98 mmol) in toluene (50 mL) was dropwise addedduring 30 min, and then the reaction proceeded at 0° C. for additional 1h. The reaction mixture was partitioned between water (50 mL) and EA(100 mL), the organic phase was separated and dried over MgSO₄, filteredand concentrated. The residue was purified by a silica gel flash columnwith PE/EA=10:1 to afford the titled compound (6 g, 79%) as a colorlessoil.

Intermediate Compound 76″: 4-hydroxybutyl 4-methylbenzyl carbonate

4-methylbenzyl carbonochloridate (3 g, 16.30 mmol) in DCM (20 mL) wasdropwise added to a stirred solution of Et₃N (5 g, 49.50 mmol) andbutane-1,4-diol (4.4 g, 48.89 mmol) in DCM (40 mL) at 0° C. during 15min. The reaction was stirred at 25° C. for 16 h. After that, thereaction mixture was diluted with water (30 mL) and the aqueous phasewas separated. The resulting organic phase was washed with brine (15mL), dried over Na₂SO₄ and concentrated, the residue was purified by asilica gel flash column with PE/EA=3:1 to afford the titled compound(700 mg, 18%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=7.28 (d, J=8.0 Hz, 2H), 7.17 (d, J=7.6 Hz, 2H), 5.11 (s, 2H),4.18 (t, J=6.4 Hz, 2H), 3.67 (t, J=6.4 Hz, 2H), 2.35 (s, 3H), 1.80-1.73(m, 2H), 1.68-1.61 (m, 2H).

Compound 76: 4-((4-methylbenzyl)oxycarbonyloxy)butanoic acid

Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl4-methylbenzyl carbonate (700 mg, 2.94 mmol) and Celite® (diatomaceousearth, 1.4 g) in acetone (10 mL) at 0° C. The reaction proceeded at 0°C. over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of isopropanol, dilutedwith EA (20 mL), and then filtered. The filtered cake was washed with EA(10 mL) and the combined filtrate was washed with brine (10 mL×2), driedover Na₂SO₄ and concentrated. The residue was purified by a silica gelflash column with PE/EA=2:1 to afford the titled compound (400 mg, 54%)as crystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=7.28 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.11 (s, 2H), 4.20 (t,J=6.4 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H), 2.35 (s, 3H), 2.03-1.96 (m, 2H).

Example 1-77 Intermediate Compound 77′: 4-hydroxybutyl(tetrahydro-2H-pyran-4-yl) carbonate

A solution of tetrahydro-2H-pyran-4-ol (1.0 g, 9.8 mmol) and Et₃N (1.2g, 11.8 mmol) in DCM (10 mL) was added dropwise to solution oftriphosgene (1.0 g, 3.2 mmol) in DCM (10 mL) at 0° C. After the additionis complete, the reaction was stirred at 0° C. for 1 h. After that, theabove slurry was added dropwise to the suspension of butane-1,4-diol(2.7 g, 29.4 mmol) in DCM (10 mL) at 0° C. The resulting mixture waswarmed up gradually to 25° C. and stirred for 16 h. The reaction wasquenched by water (10 mL) and separated. The organic phase was driedover Na₂SO₄, filtered and concentrated. The residue was purified by asilica gel flash column with PE/EA=10:1-1:1 to afford the titledcompound (380 mg, 18%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=4.82-4.78 (m, 1H), 4.18 (t, J=6.4 Hz, 2H), 3.97-3.92(m, 2H), 3.69 (t, J=6.2 Hz, 2H), 3.70-3.53 (m, 2H), 2.06-1.93 (m, 2H),1.87-1.59 (m, 6H).

Compound 77: 4-((tetrahydro-2H-pyran-4-yl)oxycarbonyloxy)butanoic acid

Jones reagent was added dropwise to a stirred mixture of 4-hydroxybutyl(tetrahydro-2H-pyran-4-yl) carbonate (300 mg, 1.4 mmol) and Celite®(diatomaceous earth, 0.6 g) in acetone (6 mL). The reaction proceeded at0° C. over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of isopropanol, dilutedwith EA (20 mL), and then filtered. The filtered cake was washed with EA(20 mL) and the combined filtrate was washed with brine (10 mL×2), driedover Na₂SO₄ and concentrated. The residue was purified by a silica gelflash column with PE/EA=50:1-5:1 to afford the titled compound (110 mg,34%) as crystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃as solvent to characterize the titled compound, results are as follows:δ=4.84-4.77 (m, 1H), 4.20 (t, J=6.4 Hz, 2H), 4.03-3.86 (m, 2H),3.64-3.44 (m, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.05-1.88 (m, 4H), 1.79-1.70(m, 2H).

Example 1-78 Intermediate Compound 78′: tert-butyl (4-hydroxybutyl)carbonate

(Boc)₂O (2.05 g, 9.4 mmol) and DMAP (100 mg) was added to a stirredsolution of butane-1,4-diol (10 g, 111.11 mmol) in DCM (100 mL). Thereaction was stirred at 25° C. for 16 h. After that, the reactionmixture was diluted with saturated aqueous NH₄Cl (20 mL) and stirred for5 min. The aqueous phase was separated and extracted with DCM (20 mL).The combined organic phase was washed with saturated brine (30 mL),dried over anhydrous Na₂SO₄ and evaporated. The residue was purified bya silica gel flash column with Hex/EA=10:1 to yield the titled compound(1 g, 56%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=4.10 (t, J=6.6 Hz, 2H), 3.68 (q, J=6.0 Hz, 2H), 1.79-1.72 (m,2H), 1.69-1.62 (m, 2H), 1.48 (s, 9H), 1.34 (t, J=5.2 Hz, 1H).

Compound 78: 4-(tert-butoxycarbonyloxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of tert-butyl(4-hydroxybutyl) carbonate (800 mg, 4.21 mmol) and Celite® (diatomaceousearth, 2 g) in acetone (10 mL) at 0° C. The reaction proceeded at 0° C.for over 1 h and the reaction progress was monitored by TLC. Aftercompletion, the reaction was quenched with drops of iPrOH, diluted withEA (10 mL) and then filtered. The filtered cake was washed with EA (5mL) and the combined filtrate was washed with saturated brine (2 mL×2),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby a silica gel flash column with Hex/EA=10:1-6:1 to yield the titledcompound (500 mg, 58%) as a colorless oil. ¹H NMR was performed at 400MHz with CDCl₃ as solvent to characterize the titled compound, resultsare as follows: δ=4.12 (t, J=6.2 Hz, 2H), 2.49 (t, J=7.4 Hz, 2H),2.03-1.96 (m, 2H), 1.48 (s, 9H).

Example 1-79 Intermediate Compound 79′: benzyl4-(chlorocarbonyloxy)butanoate

Pyridine (305 mg, 3.9 mmol) was slowly added to a solution oftriphosgene (976 mg, 3.4 mmol) in toluene (10 mL) at 0° C. and stirredfor 0.5 h. A solution of benzyl 4-hydroxybutanoate (500 mg, 2.6 mmol) intoluene (5 mL) was added to the above formed slurry at 0° C. Thereaction was allowed to warm up and stirred at 25° C. for 1.5 h. Afterthat, the reaction mixture was partitioned between water (15 mL) and EA(15 mL). The organic layer was separated, washed with brine (10 mL),dried over Na₂SO₄ and filtered. The filtrated was concentrated to yielda light yellow oil, which was purified by a silica gel flash column withPE/EA=20:1-5:1 to afford the titled compound (490 mg, 74%) as colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.43-7.27(m, 5H), 5.14 (s, 2H), 4.37 (t, J=6.2 Hz, 2H), 2.50 (t, J=7.2 Hz, 2H),2.12-2.05 (m, 2H).

Intermediate Compound 79″: benzyl 4-((1-methylpiperidin-4-yl)oxycarbonyloxy) butanoate

A solution of benzyl 4-(chlorocarbonyloxy)butanoate (500 mg, 1.95 mmol)and Et₃N (395 mg, 3.91 mmol) in DCM (5 mL) was added dropwise to astirred solution of 1-methylpiperidin-4-ol (225 mg, 1.96 mmol) in DCM (5mL) at 0° C. during 10 min. After that, the reaction mixture was dilutedwith water (5 mL), the resulting aqueous phase was separated andextracted with DCM (5 mL). The combined organic phase was washed withbrine (5 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by prep-HPLC to afford the titled compound (240 mg, 37%) asa colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solventto characterize the titled compound, results are as follows: δ=7.43-7.29(m, 5H), 5.12 (s, 2H), 4.77 (br. s., 1H), 4.18 (t, J=6.2 Hz, 2H),2.84-2.65 (m, 4H), 2.51-2.47 (m, 5H), 2.18-1.99 (m, 4H), 1.98-1.83 (m,2H).

Compound 79: 4-((1-methylpiperidin-4-yl)oxycarbonyloxy)butanoic acid

Pd/C (40 mg) was added to a solution of benzyl4-((1-methylpiperidin-4-yl)oxycarbonyloxy)butanoate (200 mg, 0.6 mmol)in methanol (3 mL). The mixture was stirred at 25° C. under H₂atmosphere for 16 h. After that, the mixture was filtered throughCelite® (diatomaceous earth) and the filtered cake was washed withmethanol (3 mL). The combined filtrate was concentrated, the residue waspurified by prep-HPLC to afford the titled compound (15 mg, 10%) ascrystalline solids. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=4.92 (br. s., 1H), 4.22 (t, J=6.4 Hz, 2H), 3.19 (br. s., 4H), 2.77 (s,3H), 2.44 (t, J=7.2 Hz, 2H), 2.35-2.20 (m, 2H), 2.13-2.08 (m, 2H),2.05-1.98 (m, 2H).

Example 1-80 Intermediate Compound 80′: 4-hydroxybutyl 2-chloroacetate

A solution of 2-chloroacetyl chloride (5 g, 44.25 mmol) in DCM (10 mL)dropwise during 10 min was added to a stirred solution ofbutane-1,4-diol (19.9 g, 221.11 mmol) and Et₃N (8.9 g, 88.5 mmol) in DCM(40 mL) at 0° C. The reaction was allowed to warm up gradually andstirred at 0-25° C. over 16 h. After that, the reaction mixture wasdiluted with H₂O (20 mL) and stirred for 5 min. The aqueous phase wasseparated and extracted with DCM (20 mL). The combined organic phase waswashed with saturated brine (30 mL), dried over anhydrous Na₂SO₄ andevaporated. The residue was purified by a silica gel flash column withHex/EA=5:1 to yield the titled compound (3.2 g, 44%) as a colorless oil.¹H NMR was performed at 400 MHz with CDCl₃ as solvent to characterizethe titled compound, results are as follows: δ=4.24 (t, J=6.6 Hz, 2H),4.07 (s, 2H), 3.69 (t, J=6.4 Hz, 2H), 1.82-1.75 (m, 2H), 1.68-1.61 (m,2H).

Intermediate Compound 80″: 2-(4-hydroxybutoxy)-2-oxoethyl2-ethylbenzoate

Et₃N (365 mg, 3.61 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg,1.81 mmol) was added to a stirred solution of 2-ethylbenzoic acid (542mg, 3.61 mmol) in acetone (10 mL). The reaction was stirred at 50° C.for 5 h. After that, the reaction mixture was partitioned between DCM(20 mL) and H₂O (10 mL). The aqueous phase was separated and extractedwith DCM (10 mL). The combined organic phase was washed with saturatedbrine (20 mL), dried over anhydrous Na₂SO₄ and evaporated. The residuewas purified by a silica gel flash column with Hex/EA=6:1 to yield thetitled compound (175 mg, 35%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=8.02-7.95 (m, 1H), 7.49-7.44 (m, 1H),7.32-7.24 (m, 2H), 4.83 (s, 2H), 4.25 (t, J=6.4 Hz, 2H), 3.67 (t, J=6.4Hz, 2H), 3.08-2.97 (m, 2H), 1.81-1.74 (m, 2H), 1.67-1.60 (m, 2H),1.28-1.22 (m, 3H).

Compound 80: 4-(2-(2-ethylbenzoyloxy)acetoxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of2-(4-hydroxybutoxy)-2-oxoethyl 2-ethylbenzoate (170 mg, 0.61 mmol) andCelite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column withHex/EA=10:1-5:1 to yield the titled compound (90 mg, 51%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.96 (d,J=7.6 Hz, 1H), 7.46 (t, J=7.0 Hz, 1H), 7.31-7.25 (m, 2H), 4.83 (s, 2H),4.28 (t, J=6.2 Hz, 2H), 3.00 (q, J=7.6 Hz, 2H), 2.47 (t, J=7.4 Hz, 2H),2.06-1.99 (m, 2H), 1.24 (t, J=7.4 Hz, 3H).

Example 1-81 Intermediate Compound 81′: 2-(4-hydroxybutoxy)-2-oxoethyl2,4-dimethylbenzoate

Et₃N (364 mg, 3.6 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg, 1.81mmol) to a stirred solution of 2,4-dimethylbenzoic acid (405 mg, 2.7mmol) in acetone (10 mL). The reaction was stirred at 50° C. for 5 h.After that, the reaction mixture was partitioned between DCM (20 mL) andH₂O (10 mL). The aqueous phase was separated and extracted with DCM (10mL). The combined organic phase was washed with saturated brine (20 mL),dried over anhydrous Na₂SO₄ and evaporated. The residue was purified bya silica gel flash column with Hex/EA=6:1 to yield the titled compound(350 mg, 69%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=7.92 (d, J=8.0 Hz, 1H), 7.08-7.06 (m, 2H), 4.81 (s, 2H), 4.24(t, J=6.6 Hz, 2H), 3.67 (t, J=6.2 Hz, 2H), 2.59 (s, 3H), 2.36 (s, 3H),1.80-1.73 (m, 2H), 1.66-1.60 (m, 2H), 1.44 (br. s., 1H).

Compound 81: 4-(2-(2,4-dimethylbenzoyloxy)acetoxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of2-(4-hydroxybutoxy)-2-oxoethyl 2,4-dimethylbenzoate (300 mg, 1.07 mmol)and Celite® (diatomaceous earth, 2 g) in acetone (10 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column withHex/EA=10:1-5:1 to yield the titled compound (150 mg, 48%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.92 (d,J=8.4 Hz, 1H), 7.18-7.06 (m, 2H), 4.81 (s, 2H), 4.27 (t, J=6.2 Hz, 2H),2.58 (s, 3H), 2.47 (t, J=7.4 Hz, 2H), 2.36 (s, 3H), 2.06-2.00 (m, 2H).

Example 1-82 Intermediate Compound 82′: 2-(4-hydroxybutoxy)-2-oxoethyl2,3-dimethoxybenzoate

Et₃N (364 mg, 3.6 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg, 1.81mmol) was added to a stirred solution of 2,3-dimethoxybenzoic acid (655mg, 3.6 mmol) in acetone (10 mL). The reaction was stirred at 50° C. for5 h. After that, the reaction mixture was partitioned between DCM (20mL) and H₂O (10 mL). The aqueous phase was separated and extracted withDCM (10 mL). The combined organic phase was washed with saturated brine(20 mL), dried over anhydrous Na₂SO₄ and evaporated. The residue waspurified by a silica gel flash column with Hex/EA=2:1 to yield thetitled compound (200 mg, 35%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.43 (dd, J=2.4, 6.8 Hz, 1H), 7.14-7.08 (m,2H), 4.84 (s, 2H), 4.25 (t, J=6.5 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H),3.67 (t, J=6.2 Hz, 2H), 1.81-1.74 (m, 2H), 1.67-1.60 (m, 2H).

Compound 82: 4-(2-(2,3-dimethoxybenzoyloxy)acetoxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of2-(4-hydroxybutoxy)-2-oxoethyl 2,3-dimethoxybenzoate (200 mg, 0.64 mmol)and Celite® (diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. Thereaction proceeded at 0° C. for over 1 h and the reaction progress wasmonitored by TLC. After completion, the reaction was quenched with dropsof iPrOH, diluted with EA (10 mL) and then filtered. The filtered cakewas washed with EA (5 mL) and the combined filtrate was washed withsaturated brine (2 mL×2), dried over anhydrous Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column withHex/EA=5:1-2:1 to yield the titled compound (100 mg, 48%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.43 (dd,J=2.6, 7.0 Hz, 1H), 7.14-7.09 (m, 2H), 4.84 (s, 2H), 4.27 (t, J=6.0 Hz,2H), 3.93 (s, 3H), 3.89 (s, 3H), 2.47 (t, J=7.2 Hz, 2H), 2.06-1.99 (m,2H).

Example 1-83 Intermediate Compound 83′: 2-(4-hydroxybutoxy)-2-oxoethylbenzoate

Et₃N (364 mg, 3.6 mmol) and 4-hydroxybutyl 2-chloroacetate (300 mg, 1.81mmol) was added to a stirred solution of benzoic acid (439 mg, 3.6 mmol)in acetone (10 mL). The reaction was stirred at 50° C. for 5 h. Afterthat, the reaction mixture was partitioned between DCM (20 mL) and H₂O(10 mL). The aqueous phase was separated and extracted with DCM (10 mL).The combined organic phase was washed with saturated brine (20 mL),dried over anhydrous Na₂SO₄ and evaporated. The residue was purified bya silica gel flash column with Hex/EA=6:1 to yield the titled compound(260 mg, 57%) as a colorless oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=8.10 (d, J=7.2 Hz, 2H), 7.60 (t, J=7.4 Hz, 1H), 7.47 (t,J=7.8 Hz, 2H), 4.85 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 3.67 (t, J=6.2 Hz,2H), 1.80-1.73 (m, 2H), 1.66-1.59 (m, 2H).

Compound 83: 4-(2-(benzoyloxy)acetoxy)butanoic acid

Jones reagent was added in portions to a stirred mixture of2-(4-hydroxybutoxy)-2-oxoethyl benzoate (250 mg, 0.99 mmol) and Celite®(diatomaceous earth, 2 g) in acetone (5 mL) at 0° C. The reactionproceeded at 0° C. for over 1 h and the reaction progress was monitoredby TLC. After completion, the reaction was quenched with drops of iPrOH,diluted with EA (10 mL) and then filtered. The filtered cake was washedwith EA (5 mL) and the combined filtrate was washed with saturated brine(2 mL×2), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with Hex/EA=10:1-5:1 to yield thetitled compound (140 mg, 53%) as a white solid. ¹H NMR was performed at400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=8.10 (d, J=7.2 Hz, 2H), 7.60 (t, J=7.4 Hz,1H), 7.47 (t, J=7.8 Hz, 2H), 4.85 (s, 2H), 4.27 (t, J=6.2 Hz, 2H), 2.46(t, J=7.4 Hz, 2H), 2.05-1.98 (m, 2H).

Example 1-84 Intermediate Compound 84′: benzyl4-(2-chloroacetoxy)butanoate

A solution of 2-chloroacetyl chloride (865 mg, 7.65 mmol) in DCM (10 mL)was added to a stirred solution of benzyl 4-hydroxybutanoate (1350 mg,6.96 mmol) and Et₃N (1406 mg, 13.92 mmol) in DCM (10 mL) at 0° C. during10 min. The reaction was stirred at 25° C. for 16 h. After completion,the reaction mixture was diluted with water (10 mL). The organic phasewas collected, washed with brine (5 mL), dried over Na₂SO₄ andconcentrated. The residue was purified by a silica gel flash column withPE/EA=8:1 to afford the titled compound (977 mg, 52%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.41-7.30(m, 5H), 5.13 (s, 2H), 4.24 (t, J=6.4 Hz, 2H), 4.02 (s, 2H), 2.47 (t,J=7.4 Hz, 2H), 2.07-2.00 (m, 2H).

Intermediate Compound 84′: benzyl4-(2-2-(tert-butoxycarbonyl)aminoacetoxyacetoxy)butanoate

A solution of 2-(tert-butoxycarbonylamino)acetic acid (654 mg, 3.74mmol), Et₃N (686 mg, 6.79 mmol) and benzyl 4-(2-chloroacetoxy)butanoate(917 mg, 3.40 mmol) in acetone (10 mL) was stirred at 50° C. for 16 h.After that, the mixture was diluted with EA (30 mL) and water (10 mL),the aqueous phase was separated and the organic phase was washed withbrine (10 mL), dried over Na₂SO₄ and concentrated. The residue waspurified by a silica gel flash column with PE/EA=5:1 to afford thetitled compound (1.16 g, 84%) as a colorless oil. ¹H NMR was performedat 400 MHz with CDCl₃ as solvent to characterize the titled compound,results are as follows: δ=7.41-7.32 (m, 5H), 5.13 (s, 2H), 5.01 (br. s.,1H), 4.64 (s, 2H), 4.22 (t, J=6.4 Hz, 2H), 4.04 (d, J=5.6 Hz, 2H), 2.45(t, J=7.2 Hz, 2H), 2.05-1.98 (t, J=6.8 Hz, 2H), 1.45 (s, 9H).

Intermediate Compound 84′″:2,2-dimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic acid

Pd/C (100 mg) was added to a stirred solution of benzyl4-(2-2-(tert-butoxycarbonyl)aminoacetoxyacetoxy)butanoate (1 g, 2.44mmol) in THF (10 mL), the mixture was stirred at 25° C. under H₂atmosphere for 16 h. After that, the reaction mixture was filteredthrough Celite® (diatomaceous earth). The filtered cake was washed withEA (5 mL), the combined filtrate was concentrated. The residue waspurified by prep-HPLC to afford the titled compound (600 mg, 77%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=5.11 (br.s., 1H), 4.70 (s, 2H), 4.24 (t, J=5.8 Hz, 2H), 4.11 (d, J=6.0 Hz, 2H),2.46 (t, J=6.8 Hz, 2H), 2.10-2.02 (m, 2H), 1.46 (s, 9H).

Compound 84: 4-(2-(2-aminoacetoxy)acetoxy)butanoic acid

2,2-dimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic acid(600 mg, 1.88 mmol) was dissolved in HCl/EA (6 mL, ˜2 M) and thesolution was stirred at 25° C. for 16 h. After that, the reactionmixture was filtered, the collected solid was washed with Et₂O (5 mL) toafford the titled compound (450 mg, 94%) as crystalline solids in HClsalt form. ¹H NMR was performed at 400 MHz with D₂O as solvent tocharacterize the titled compound, results are as follows: δ=4.84 (s,2H), 4.23 (t, J=6.0 Hz, 2H), 4.03 (s, 2H), 2.43 (t, J=7.2 Hz, 2H),1.98-1.91 (m, 2H).

Example 1-85 Intermediate Compound 85′: benzyl4-(2-chloropropanoyloxy)butanoate

A solution of 2-chloropropanoyl chloride (1080 mg, 8.50 mmol) in DCM (10mL) was dropwise added to a stirred solution of benzyl4-hydroxybutanoate (1.5 g, 7.73 mmol) Et₃N (1562 mg, 15.47 mmol) in DCM(10 mL) at 0° C., the reaction was stirred at 25° C. for 16 h. Afterthat, the reaction mixture was diluted with water (10 mL), the aqueousphase was separated and the organic phase was washed with brine (10 mL),dried over Na₂SO₄ and concentrated. The residue was purified by a silicagel flash column with PE/EA=8:1 to afford the titled compound (1.38 g,63%) as a colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=7.41-7.30 (m, 5H), 5.13 (s, 2H), 4.36 (q, J=7.0 Hz, 1H), 4.22 (t,J=6.0 Hz, 2H), 2.48 (t, J=7.4 Hz, 2H), 2.07-2.00 (m, 2H), 1.67 (d, J=6.8Hz, 3H).

Intermediate Compound 85″: benzyl4-(2-(2-(tert-butoxycarbonyl)aminoacetoxy)propanoyloxy)butanoate

Et₃N (782 mg, 7.75 mmol) and NaI (20 mg) was added to a stirred solutionof 2-(tert-butoxycarbonylamino)acetic acid (746 mg, 4.26 mmol) andbenzyl 4-(2-chloropropanoyloxy)butanoate (1.1 g, 3.87 mmol) in DMF (15mL), the reaction mixture was stirred at 70° C. for 16 h. After that,the mixture was concentrated, the residue was partitioned between EA (20mL) and water (10 mL). The aqueous phase was separated, the organicphase was washed with brine (10 mL), dried over Na₂SO₄ and concentrated.The residue was purified by a silica gel flash column with PE/EA=5:1 toafford the titled compound (1.1 g, 69%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.43-7.29 (m, 5H), 5.15-5.09 (m,3H), 5.00 (br. s., 1H), 4.19 (t, J=6.2 Hz, 2H), 4.06 (dd, J=6.0, 18.4Hz, 1H), 3.93 (dd, J=5.0, 14.2 Hz, 1H), 2.44 (t, J=7.2 Hz, 2H),2.03-1.97 (m, 2H), 1.49 (d, J=6.8 Hz, 3H), 1.45 (s, 9H).

Intermediate Compound 85′″:2,2,9-trimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic acid

Pd/C (100 mg) was added to a stirred solution of benzyl4-(2-(2-(tert-butoxycarbonyl)aminoacetoxy)propanoyloxy)butanoate (1.1 g,2.60 mmol) in THF (10 mL), the reaction mixture was stirred at 25° C.under H₂ atmosphere for 16 h. After that, the reaction mixture wasfiltered through Celite® (diatomaceous earth) and the filtered cake waswashed with EA (5 mL). The combined filtrate was concentrated, theresidue was purified by prep-HPLC to afford the titled compound (800 mg,92%) as a colorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ assolvent to characterize the titled compound, results are as follows:δ=5.21 (q, J=6.8 Hz, 1H), 5.12 (br. s., 1H), 4.29-4.09 (m, 3H), 3.94(dd, J=4.6, 18.8 Hz, 1H), 2.45 (t, J=6.8 Hz, 2H), 2.09-1.98 (m, 2H),1.50 (d, J=7.2 Hz, 3H), 1.46 (s, 9H).

Compound 85: 4-(2-(2-aminoacetoxy)propanoyloxy)butanoic acid

2,2,9-trimethyl-4,7,10-trioxo-3,8,11-trioxa-5-azapentadecan-15-oic acid(770 mg, 2.31 mmol) was dissolved in HCl/EA (10 mL, ˜2 M) at 0° C. andthe solution was stirred at 25° C. for 16 h. After that, the reactionmixture was concentrated, the residue was purified by prep-HPLC toafford the titled compound (48 mg, 9%) as a colorless oil in HCl saltform. ¹H NMR was performed at 400 MHz with D₂O as solvent tocharacterize the titled compound, results are as follows: δ=5.26 (d,J=7.2 Hz, 1H), 4.23 (dt, J=2.8, 6.0 Hz, 2H), 4.00 (d, J=1.6 Hz, 2H),2.45 (t, J=7.0 Hz, 2H), 2.01-1.91 (m, 2H), 1.50 (d, J=7.2 Hz, 3H).

Example 1-86 Intermediate Compound 86′: benzyl4-(2-(2-acetamidoacetoxy)propanoyloxy)butanoate

A mixture of benzyl 4-(2-chloropropanoyloxy)butanoate (500 mg, 1.76mmol), 2-acetamidoacetic acid (260 mg, 2.22 mmol), NaI (138 mg, 0.92mmol) and Et₃N (0.52 mL, 3.69 mmol) in DMF (5 mL) was stirred at 80° C.for 16 h. The reaction mixture was filtered and the filtrate wasconcentrated. The residue was purified by silica gel flash column withPE/EA=5:1 to afford the titled compound (500 mg, 78%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.39-7.31(m, 5H), 6.01 (br. s., 1H), 5.13 (s, 2H), 5.10 (t, J=3.2 Hz, 1H),4.25-4.18 (m, 3H), 4.03 (dd, J=4.8, 18.8 Hz, 1H), 2.44 (t, J=7.4 Hz,2H), 2.04-1.97 (m, 5H), 1.50 (d, J=7.2 Hz, 3H).

Compound 86: 4-(2-(2-acetamidoacetoxy)propanoyloxy)butanoic acid

Pd/C (150 mg) was added to a stirred solution of benzyl4-(2-(2-acetamidoacetoxy)propanoyloxy)butanoate (500 mg, 1.37 mmol) inTHF (10 mL), the reaction was stirred at 25° C. for 16 h under H₂atmosphere. After that, the reaction mixture was filtered and thefiltrate was concentrated. The residue was purified by a silica gelflash column with PE/EA=1:50 to afford the titled compound (280 mg, 74%)as a white solid. ¹H NMR was performed at 400 MHz with d₆-DMSO assolvent to characterize the titled compound, results are as follows:δ=12.15 (s, 1H), 8.34 (t, J=5.6 Hz, 1H), 5.02 (q, J=6.8 Hz, 1H),4.12-4.06 (m, 2H), 3.93 (dd, J=6.2, 17.8 Hz, 1H), 3.84 (dd, J=6.0, 17.6Hz, 1H), 2.28 (t, J=7.2 Hz, 2H), 1.85 (s, 3H), 1.84-1.77 (m, 2H), 1.41(d, J=7.2 Hz, 3H).

Example 1-87 Intermediate Compound 87′: benzyl4-((1-chloroethoxy)carbonyloxy)butanoate

1-chloroethyl carbonochloridate (1.0 g, 7.2 mmol) was added dropwise toa solution of benzyl 4-hydroxybutanoate (1.0 g, 5.2 mmol) and Et₃N (1.1mL, 1.7 mmol) in DCM (10 mL) over 5 min at −5-0° C. After that, thereaction was quenched by water (5 mL). The organic layer was separated,dried over Na₂SO₄ and filtered. The filtrate was concentrated and theresidue was purified by silica gel flash column with PE/EA=20:1-5:1 toafford titled compound (680 mg, 44%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=7.39-7.33 (m, 5H), 6.41 (q, J=5.6Hz, 1H), 5.13 (s, 2H), 4.26 (t, J=6.4 Hz, 2H), 2.49 (t, J=7.4 Hz, 2H),2.09-2.02 (m, 2H), 1.82 (d, J=6.0 Hz, 3H).

Intermediate Compound 87″: benzyl4-((1-acetoxyethoxy)carbonyloxy)butanoate

A solution of benzyl 4-((1-chloroethoxy)carbonyloxy)butanoate (180 mg,598 μmol), acetic acid (720 mg, 12.0 mmol) and Et₃N (151 mg, 1.5 mmol)in acetone (4 mL) was heated under reflux for 2 days. The reaction wasdiluted with EA (20 mL) and washed with water (10 mL). The organic layerwas separated, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated and the residue was purified by a silica gel flash columnwith PE/EA=10:1-3:1 to afford the titled compound (120 mg, 64%) as acolorless oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=7.38-7.33(m, 5H), 6.74 (q, J=3.6 Hz, 1H), 5.13 (s, 2H), 4.21 (t, J=6.2 Hz, 2H),2.48 (t, J=4.8 Hz, 2H), 2.08 (s, 3H), 2.06-2.01 (m, 2H), 1.51 (d, J=3.6Hz, 3H).

Compound 87: 4-((1-acetoxyethoxy)carbonyloxy)butanoic acid

Pd/C (10 mg) was added to a mixture of benzyl4-((1-acetoxyethoxy)carbonyloxy)butanoate (110 mg, 339 μmol) in EA (2mL). The reaction was stirred under H₂ atmosphere for 16 h at 25° C.After that, the reaction mixture was filtered and the filtrate wasconcentrated to afford the titled compound (70 mg, 88%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=6.75 (q,J=5.2 Hz, 1H), 4.23 (t, J=6.2 Hz, 2H), 2.49 (t, J=7.2 Hz, 2H), 2.09 (s,3H), 2.06-1.99 (m, 2H), 1.52 (d, J=5.2 Hz, 3H).

Example 1-88 Intermediate Compound 88′: benzyl4-(1-(isobutyryloxy)ethoxycarbonyloxy)butanoate

A solution of benzyl 4-((1-chloroethoxy)carbonyloxy)butanoate (300 mg,998 μmol), isobutyric acid (879 mg, 10.0 mmol), NaI (179 mg, 1.2 mmol)and Et₃N (121 mg, 1.2 mmol) in acetone (6 mL) was heated under refluxfor 2 days. After that, the reaction mixture was diluted with EA (20 mL)and washed with saturated NaHCO₃ (10 mL). The organic layer wasseparated, dried over Na₂SO₄ and filtered. The filtrate was concentratedand the residue was purified by a silica gel column with PE/EA=50:1-5:1to afford the titled compound (300 mg, 85%) as a colorless oil. ¹H NMRwas performed at 400 MHz with CDCl₃ as solvent to characterize thetitled compound, results are as follows: δ=7.42-7.29 (m, 5H), 6.74 (q,J=5.2 Hz, 1H), 5.12 (s, 2H), 4.21 (t, J=6.2 Hz, 2H), 2.58-2.51 (m, 1H),2.48 (t, J=7.2 Hz, 2H), 2.06-2.00 (m, 2H), 1.51 (d, J=5.6 Hz, 3H), 1.17(d, J=7.2 Hz, 6H).

Compound 88: 4-(1-(isobutyryloxy)ethoxycarbonyloxy)butanoic acid

Pd/C (28 mg) was added to a mixture of benzyl4-(1-(isobutyryloxy)ethoxycarbonyloxy)butanoate (280 mg, 795 μmol) in EA(6 mL). The reaction was stirred under H₂ atmosphere for 16 h at 25° C.After that, the reaction mixture was filtered and the filtrate wasconcentrated to afford the titled compound (200 mg, 96%) as a colorlessoil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=6.74 (q,J=5.6 Hz, 1H), 4.23 (t, J=6.0 Hz, 2H), 2.60-2.53 (m, 1H), 2.49 (t, J=7.2Hz, 2H), 2.06-1.99 (m, 2H), 1.52 (d, J=5.2 Hz, 3H), 1.18 (d, J=6.8 Hz,6H).

Example 1-89 Intermediate Compound 89′: 1-((4-benzyloxy-4-oxobutoxy)carbonyloxy)ethyl benzoate

A solution of benzyl 4-((1-chloroethoxy)carbonyloxy)butanoate (300 mg,998 μmol), benzoic acid (244 mg, 2.0 mmol), NaI (179 mg, 1.2 mmol) andEt₃N (121 mg, 1.2 mmol) in acetone (6 mL) was heated under reflux for 3days. After that, the reaction was diluted with EA (20 mL) and washedwith saturated NaHCO₃ (10 mL). The organic layer was separated, driedover Na₂SO₄ and filtered. The filtrate was concentrated and the residuewas purified by a silica gel flash column with PE/EA=100:1-10:1 toafford the titled compound (240 mg, 62%) as a colorless oil. ¹H NMR wasperformed at 400 MHz with CDCl₃ as solvent to characterize the titledcompound, results are as follows: δ=8.05 (d, J=7.2 Hz, 2H), 7.58 (t,J=7.4 Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.39-7.28 (m, 5H), 7.02 (q, J=5.6Hz, 1H), 5.11 (s, 2H), 4.32-4.12 (m, 2H), 2.48 (t, J=7.6 Hz, 2H),2.07-1.97 (m, 2H), 1.65 (d, J=5.6 Hz, 3H).

Compound 89: 4-(1-(benzoyloxy)ethoxycarbonyloxy)butanoic acid

Pd/C (20 mg) was added to a mixture of1-((4-benzyloxy-4-oxobutoxy)carbonyloxy)ethyl benzoate (200 mg, 518μmol) in EA (4 mL). The reaction was stirred under H₂ atmosphere for 16h at 25° C. After that, the reaction mixture was filtered and thefiltrate was concentrated to afford the titled compound (120 mg, 78%) asa sticky oil. ¹H NMR was performed at 400 MHz with CDCl₃ as solvent tocharacterize the titled compound, results are as follows: δ=8.06 (d,J=7.2 Hz, 2H), 7.59 (t, J=7.4 Hz, 1H), 7.45 (t, J=7.6 Hz, 2H), 7.03 (q,J=5.6 Hz, 1H), 4.24 (t, J=6.4 Hz, 2H), 2.49 (t, J=7.2 Hz, 2H), 2.06-1.99(m, 2H), 1.66 (d, J=5.6 Hz, 3H).

Example 1-90 Intermediate Compound 90′: benzyl4-(3,10,10-trimethyl-5,8-dioxo-2,4,9-trioxa-7-azaundecan-1-oyloxy)butanoate

A solution of benzyl 4-((1-chloroethoxy)carbonyloxy)butanoate (450 mg,1.5 mmol), 2-(tert-butoxycarbonylamino)acetic acid (524 mg, 3.0 mmol),NaI (449 mg, 3.0 mmol) and Et₃N (182 mg, 1.8 mmol) in acetone (10 mL)was heated under reflux for 3 days. The reaction mixture was filteredand the filtrate was concentrated. The residue was purified by a silicagel flash column with PE/EA=10:1-1:1 to afford the titled compound (390mg, 59%) as a colorless sticky oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=7.39-7.31 (m, 5H), 6.80 (q, J=5.6 Hz, 1H), 5.12 (s, 2H), 4.97(br. s., 1H), 4.21 (t, J=6.2 Hz, 2H), 4.03-3.84 (m, 2H), 2.48 (t, J=7.4Hz, 2H), 2.06-2.00 (m, 2H), 1.53 (d, J=5.2 Hz, 3H), 1.44 (s, 9H).

Intermediate Compound 90″:2,2,9-trimethyl-4,7,11-trioxo-3,8,10,12-tetraoxa-5-azahexadecan-16-oicacid

Pd/C (38 mg) was added to a mixture of benzyl4-(3,10,10-trimethyl-5,8-dioxo-2,4,9-trioxa-7-azaundecan-1-oyloxy)butanoate(380 mg, 865 μmol) in EA (8 mL). The reaction was stirred under H₂atmosphere for 16 h at 25° C. After that, the reaction mixture wasfiltered and the filtrate was concentrated to afford the titled compound(280 mg, 93%) as a sticky oil. ¹H NMR was performed at 400 MHz withCDCl₃ as solvent to characterize the titled compound, results are asfollows: δ=6.82 (q, J=5.2 Hz, 1H), 5.03 (br. s., 1H), 4.34-4.15 (m, 2H),3.96 (d, J=6.0 Hz, 2H), 2.49 (t, J=7.0 Hz, 2H), 2.13-1.96 (m, 2H), 1.54(d, J=5.6 Hz, 3H), 1.45 (s, 9H).

Compound 90: 4-(1-(2-aminoacetoxy)ethoxycarbonyloxy)butanoic acid

A solution of2,2,9-trimethyl-4,7,11-trioxo-3,8,10,12-tetraoxa-5-azahexadecan-16-oicacid (280 mg, 802 μmol) in HCl/EA (5 mL, ˜2 M) was stirred for 16 h at25° C. The precipitate was formed and filtered. The filtered cake waswashed with EA (10 mL) and then dried in vacuo to afford the titledcompound (168 mg, 84%) as a white solid in HCl salt form. ¹H NMR wasperformed at 400 MHz with D₂O as solvent to characterize the titledcompound, results are as follows: δ=6.81 (q, J=5.6 Hz, 1H), 4.22 (t,J=6.0 Hz, 2H), 3.94 (s, 2H), 2.44 (t, J=7.2 Hz, 2H), 1.98-1.92 (m, 2H),1.52 (d, J=5.2 Hz, 3H).

Example 2: Metabolic Stability Assay of the Test Compounds

Rat/Human Liver S9 Fractions Metabolic Stability Assay

The protocol for rat/human liver S9 fractions metabolic stability assayis employed to determine the half-life (T_(1/2)) of the compounds of thepresent disclosure and their releasing efficiency of converting from theprodrugs to GHB in vitro.

The following is the study outline for S9 assay: 1) For GHB releasingefficiency assay, pooled liver S9 fractions (human or rat) in mixedgender were obtained from commercial vendors (e.g., Xenotech) and storedat −80° C. prior to use. 2) A master solution in the incubation platecontaining phosphate buffer, ultra-pure H₂O, MgCl₂ solution and liver S9fraction was made to keep S9 fractions at 1 mg/mL final concentration.The mixture was pre-warmed at 37° C. water bath for 5 minutes. 3) Add 4μL of 500 μM test compound solution to the master solution plate at thefinal concentration of 5 μM test compound. The reaction was started withthe addition of 40 μL of 10 mM NADPH and carried out at 37° C. 4) 50 μLaliquots of the reaction solution were taken out and put into new platesat different time points including 0, 15, 30, 45 and 60 minutes, andincubated at 37° C. water bath with shaking at 60 rpm. The reaction wasstopped by adding 200 μL of cold quench solution (methanol containinginternal standards) at the appointed time points. The plates werecentrifuged at 3220 g at 4° C. for 40 minutes to precipitate protein. 5)100 μL of the supernatant was transferred to a new plate. Thesupernatant was diluted with water according to the LC/MS signalresponse and peak shape, mixed well and analyzed using LC/MS/MS formeasurement of test compounds and GHB. The measurement results were thenused for calculation of half-life (T_(1/2)) of the test compounds andtheir conversion efficiency into GHB in S9 fractions. GHB releasingefficiency is calculated by dividing the detected amount of GHB by thetotal amount of GHB that can be released by the test compound. Data areshown as below in Table 1.

TABLE 1 Metabolic Stability of Test Compounds in Human and Rat Liver S9Fractions GHB releasing T_(1/2) efficiency (%) Test Compounds Species(min) at 60 min point Compound 32 Human 40.43 474-(phenoxycarbonyloxy)butanoic acid Rat 8.50 74 hydrochloride salt ofCompound 57 Human 2.15 61 (S)-4-(2-amino-3-phenylpropanoyloxy) Rat 2.4869 butanoic acid hydrochloride Compound 66 Human 9.21 784-(2-acetamidoacetoxy)butanoic acid Rat 8.00 71 Compound 67 Human 83.1735 (S)-4-(2-acetamido-3- Rat 74.22 32 methylbutanoyloxy)butanoic acidCompound 64 Human 58.01 42 4-(2-isobutyramidoacetoxy)butanoic Rat 62.6630 acid Compound 89 Human 10.54 42 4-(1-(benzoyloxy)ethoxycarbonyloxy)Rat 17.48 51 butanoic acid

The in vitro GHB releasing efficiency assay employing rat/human liver S9fractions had shown that the prodrug compounds could be converted to GHBwith variable releasing efficiencies, which suggested that they would beconverted into GHB in the systemic circulation after being administeredto rat/human.

Rat/Human Hepatocytes Metabolic Stability Assay

The protocol for rat/human hepatocytes metabolic stability assay isemployed to determine the half-life (T_(1/2)) of the compounds of thepresent disclosure and their releasing efficiency of converting from theprodrugs to GHB in vitro.

The following is the study outline for hepatocytes assay: 1) For GHBreleasing efficiency assay, rat hepatocytes in male gender and humanhepatocytes in mixed gender were obtained from commercial vendors (e.g.,BioreclamationIVT) and stored at −150° C. prior to use. 2) 30 mM stocksolutions of test compounds were prepared in DMSO. Thawing medium andsupplement incubation medium (serum-free) were placed in a 37° C. waterbath for at least 15 minutes prior to use. Stock solutions were dilutedto 500 μM by combining 295 μL acetonitrile and 5 μL of 30 mM stocksolution. 3) Vials of cryopreserved hepatocytes were removed fromstorage, ensured that vials remain at cryogenic temperatures. Thepressure was removed by loosening and re-tightening the cap. The vialswere thawed in a 37° C. water bath with gently shaking. Vials were keptin water bath until all ice crystals had dissolved and were no longervisible. Vials were sprayed with 70% ethanol before being transferred toa biosafety cabinet. And then the contents were poured into the 50 mLthawing medium conical tube. Vials were centrifuged at 100 g for 10minutes at room temperature. Thawing medium was aspirated andhepatocytes were resuspended with serum-free incubation medium to yield˜1.5×10⁶ cells/mL. 4) Cell viability and density were counted using aTrypan Blue exclusion, and then cells were diluted with serum-freeincubation medium to a working cell density of 1×10⁶ viable cells/ml. 5)A portion of the hepatocytes at 1×10⁶ viable cells/mL was boiled for 10min prior to adding to the plate as negative control to eliminate theenzymatic activity so that little or no substrate turnover should beobserved. The inactivated hepatocytes were used to prepare negativesamples, which were used to exclude the misleading factor that resultedfrom instability of chemical itself. 6) Aliquots of 247.5 μL hepatocyteswere dispensed into each well of a 96-well non-coated plate. The platewas placed in the incubator on an orbital shaker at 500 rpm forapproximately 10 minutes. 7) Aliquots of 2.5 μL of the 500 μM testcompounds were added into respective wells of the non-coated 96-wellplate to start the reaction. This assay was performed in duplicate. Theplate was incubated in the incubator on an orbital shaker at 500 rpm forthe designed time points. 8) 25 μL of contents were transferred andmixed with 6 volumes (150 μL) of cold acetonitrile with internalstandard to terminate the reaction at time points of 0, 5, 15, 30, 60,90 and 120 minutes. Samples were centrifuges for 25 minutes at 3220 gand aliquots of 100 L of the supernatants were used for LC-MS/MSanalysis for measurement of test compounds and GHB. The measurementresults were then used for calculation of half-life (T_(1/2)) of thetest compounds and their conversion efficiency into GHB in hepatocytes.Data are shown as below in Table 2.

TABLE 2 Metabolic Stability of Test Compounds in Human and RatHepatocytes GHB releasing T_(1/2) efficiency (%) Test Compounds Species(min) at 120 min point Compound 58 Human 159.97 73(S)-4-(2-amino-3-methylbutanoyloxy) Rat 46.66 46 butanoic acid Compound66 Human 24.95 46 4-(2-acetamidoacetoxy)butanoic acid Rat 16.68 35Compound 67 Human 219.89 22 (S)-4-(2-acetamido-3- Rat 130.66 21methylbutanoyloxy)butanoic acid

The in vitro GHB releasing efficiency assay employing rat/humanhepatocytes had shown that prodrug compounds could be converted to GHBwith variable releasing efficiencies, which suggested that they would beconverted into GHB in the systemic circulation after being administeredto rat/human.

Rat/Human Whole Blood Metabolic Stability Assay

The protocol for rat/human whole blood metabolic stability assay isemployed to determine the releasing efficiency of the compounds of thepresent disclosure converting from the prodrugs to GHB in vitro.

The following is the study outline for whole blood assay: 1) For GHBreleasing efficiency assay, rat whole blood in mixed gender was obtainedfrom commercial vendors (e.g., SiBeiFu (Beijing) Laboratory AnimalScience and Technology Co Ltd) and human whole blood was obtained fromhealthy volunteers in mixed gender, stored at 4° C. prior to use. 2) Thestock solution of test compounds was prepared in DMSO and diluted at thefinal concentration of 500 μM. 3) 5 μL of 500 μM working solution wasspiked to 495 μL whole blood to reach a final concentration of 5 μM. Thefinal concentration of organic solvents was 1%. The assay was performedin duplicate. The reaction samples were incubated at 37° C. atapproximately 60 rpm in a water bath. 4) Aliquots of 50 μL were takenfrom the reaction samples at 0, 15, 30, 45, 60 and 120 minutes. Thereaction was stopped by the addition of 7 volumes of cold methanolcontaining internal standards. 5) All samples were vortexed for 10minutes, followed by centrifugation at 3220 g for 30 minutes toprecipitate proteins. 100 μL of the supernatant was transferred to a newplate. The supernatant was diluted with ultra pure water according tothe LC-MS signal response and peak shape. Samples were analyzed usingLC/MS/MS for measurement of test compounds and GHB. The measurementresults were then used for calculation of conversion efficiency the testcompounds into GHB in whole blood. Data are shown as below in Table 3.

TABLE 3 Metabolic Stability of Test Compounds in Human and Rat WholeBlood GHB releasing efficiency (%) at 120 min Test Compounds Speciespoint Compound 58 Human 42 (S)-4-(2-amino-3-methylbutanoyloxy) Rat 85butanoic acid Compound 66 Human 76 4-(2-acetamidoacetoxy)butanoic acidRat 100 Compound 67 Human 45 (S)-4-(2-acetamido-3-methylbutanoyloxy) Rat83 butanoic acid

The in vitro GHB releasing efficiency assay employing rat/human wholeblood had shown that prodrug compounds could be converted to GHB withvariable releasing efficiencies, which suggested that they would beconverted into GHB in the systemic circulation after being administeredto rat/human.

Example 3: Pharmacokinetic Studies

For rat pharmacokinetic studies, male Sprague-Dawley rats were housedindividually and fasted overnight before use. The animal dosingexperiments were carried out in accordance to the National Institutes ofHealth Guide to the Care and Use of Laboratory Animals and the AnimalWelfare Act. For GHB sodium salt, a single dose of 50 mg/kg wasadministered to each rat in two groups (n=3/group) via intravenous (IV)and oral (PO) administration, respectively. The vehicle used for GHBsodium salt is saline. For other test compounds, a single dose of eachtest compound was administered to each rat orally (n=3/group). Thedosage of each test compound is listed in the Table 4. The vehicle usedfor dosing test compounds was 0.5% (w/v) Sodium Carboxyl MethylCellulose (CMC-Na) in saline. Blood samples were collected at specifiedtime-points (pre-dose, 10 minutes, 0.5 hour, 1 hour, 2 hours, 4 hours, 6hours) following administration to individual rats within IV and POgroup. Blood samples were clotted on ice immediately, plasma sampleswere then isolated by centrifugation and stored frozen (−80° C.) untilfurther analysis. The concentrations of GHB and all other test compoundswere individually determined by LC/MS/MS assay. Various pharmacokineticparameters were calculated using Phoenix™ WinNonlin® software. Toquantify the bioconversion efficiency of the test compounds in thecirculation system, the relative bioavailability of GHB sodium saltafter PO administration was calculated. The values of relativebioavailability were expressed as the ratio of the AUC of GHB convertedfrom the test compounds versus the AUC of GHB sodium salt administratedvia IV alone adjusted by dose. Data are shown as below in Table 4.

TABLE 4 Rat pharmacokinetic parameters of GHB sodium salt andrepresentative compounds AUC_(last) T_(max) C_(max) Bioavailability(h*μg/mL) (min) (ng/mL) F (%) GHB sodium salt IV 25.9 100  @ 50 mg/kg PO6.7 17 7.6 26  Compound 32 PO* 12.4 10 22.4  48**4-(phenoxycarbonyloxy)butanoic acid @ 89 mg/kg Compound 58 PO* 14.3 1718.5  55** (S)-4-(2-amino-3- methylbutanoyloxy)butanoic acid @ 81 mg/kgCompound 67 PO* 7.4 10 11.1  29** (S)-4-(2-acetamido-3-methylbutanoyloxy)butanoic acid @ 97 mg/kg Compound 64 PO* 11.8 30 8.6 45** 4-(2-isobutyramidoacetoxy)butanoic acid @ 92 mg/kg Note: *measuredand calculated based on GHB, **relative bioavailability

For dog pharmacokinetic studies, male Beagle dogs were housedindividually. Dogs in oral administration groups were fasted overnightbefore use but with free access to water supply. Dogs in IV groups havefree access to food and water. The animal dosing experiments werecarried out in accordance with the National Institutes of Health Guideto the Care and Use of Laboratory Animals and the Animal Welfare Act.For GHB sodium salt, a single dose of 20 mg/kg was administered to eachdog in two groups (n=3/group) via intravenous (IV) administration. Thevehicle used for GHB sodium salt is saline. For other test compounds, asingle dose of each test compound was administered to each dog orally(n=3/group). The dosage of each test compound is listed in the Table 5.The vehicle used for dosing test compounds was 0.5% (w/v) SodiumCarboxyl Methyl Cellulose (CMC-Na) in saline. Blood samples werecollected at specified time-points (pre-dose, 5 min, 10 min, 20 min, 30min, 45 min, 1 h, 2 h, 3 h, 4 h, post-dose) following administration toindividual dogs within IV and PO group. Blood samples were clotted onice immediately, plasma samples were then isolated by centrifugation andstored frozen (−80° C.) until further analysis. The concentrations ofGHB and all other test compounds were individually determined byLC/MS/MS assay. Various pharmacokinetic parameters were calculated usingPhoenix™ WinNonlin® software. To quantify the bioconversion efficiencyof the test compounds in the circulation system, the bioavailability ofGHB sodium salt after PO administration was calculated. Data are shownas below in Table 5.

TABLE 5 Dog pharmacokinetic parameters of GHB sodium salt andrepresentative compound AUC_(last) T_(max) C_(max) Bioavailability(h*μg/mL) (min) (μg/mL) F (%) GHB sodium salt IV 35.652 100 @ 20 mg/kgCompound 58 PO* 17.866 13 32.4   51** (S)-4-(2-amino-3-methylbutanoyloxy) butanoic acid @ 32 mg/kg Note: *measured andcalculated based on GHB, **relative bioavailability

Example 4: Colonic Absorption in Rat

The purpose of the colonic absorption trial is to evaluate the effect ofthe improved transport properties of prodrugs on the resultingpharmacokinetics and distribution of GHB. The study is to be conductedby the following general procedures: GHB and the compounds of thepresent invention are each administered to groups of three to seven malerats through a bolus injection directly into the colon via theindwelling cannula. Following dosing, blood samples are obtained atintervals over 24 hours and are immediately processed to obtain theplasma at 4° C. The concentrations of GHB and all other test compoundsare individually determined by HPLC-MS/MS assay. The compounds of thepresent disclosure demonstrate more effective colonic absorption thanGHB.

While the present disclosure has been particularly shown and describedwith reference to specific embodiments (some of which are preferredembodiments), it should be understood by those skilled in the art thatvarious changes in form and detail may be made therein without departingfrom the spirit and scope of the present disclosure as disclosed herein.

What is claimed is:
 1. A compound having the chemical structure shown in Formula (IA):

or a pharmaceutically acceptable salt thereof, wherein, R_(g) is hydrogen or C₁ alkyl; and R_(h) and R_(f) are independently hydrogen, unsubstituted C₁₋₆ alkyl, C₁₋₆ alkoxylcarbonyl, or C₃₋₆ cycloalkoxylcarbonyl.
 2. The compound of claim 1, wherein at least one of R_(h) and R_(f) is hydrogen or C₁₋₃ alkyl.
 3. The compound of claim 2, wherein both R_(h) and R_(f) are hydrogen or C₁₋₃ alkyl.
 4. The compound of claim 1, wherein R_(f) is —COR⁵, and R⁵ is C₁₋₃ alkoxyl or C₅₋₆ cycloalkyloxyl.
 5. The compound of claim 1, wherein both R_(h) and R_(f) are hydrogen.
 6. The compound of claim 5, wherein the molecular weight of the compound is no more than 450 Da.
 7. The compound of claim 5, wherein a hydrogen comprises protium or deuterium.
 8. The compound of claim 5, wherein the compound can be converted to gamma-hydroxybutyric acid and enter into the human circulatory system through a biological process after oral administration.
 9. A method of treating a subject in need thereof, wherein the method comprises administering to the subject a pharmaceutically effective amount of the compound of claim 5, wherein the subject suffers from a disease or condition selected from narcolepsy, excessive daytime sleepiness, cataplexy, fibromyalgia, chronic fatigue, and tardive dyskinesia.
 10. The method of claim 9, wherein the disease or condition is narcolepsy, excessive daytime sleepiness, or cataplexy.
 11. The method of claim 9, wherein the administration is conducted no more than two times per day.
 12. The method of claim 9, wherein the administration is via oral administration.
 13. The method of claim 9, wherein the compound is formulated in a unit dosage form.
 14. The method of claim 12, wherein administering the compound orally comprises administering the compound in an emulsion, syrup, elixir, suspension, slurry, or solution.
 15. A pharmaceutical composition comprising: the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
 16. The pharmaceutical composition of claim 15, wherein both R_(h) and R_(f) are hydrogen.
 17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is a solid.
 18. The pharmaceutical composition of claim 16, wherein the pharmaceutically acceptable carrier comprises a solvent for dissolving or dispersing the compound.
 19. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is formulated in a unit dosage form.
 20. The pharmaceutical composition of claim 19, wherein the compound of Formula (IA) is present in the unit dosage form in an amount from 1 gram to 18 grams.
 21. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated in a sustained release form.
 22. The method of claim 10, wherein the disease or condition is narcolepsy.
 23. The method of claim 10, wherein the disease or condition is excessive daytime sleepiness.
 24. The method of claim 10, wherein the disease or condition is cataplexy.
 25. The method of claim 14, wherein administering the compound orally comprises administering the compound in a solution.
 26. The method of claim 13, wherein the compound of Formula (IA) is present in the unit dosage form in an amount from 1 gram to 18 grams.
 27. The compound of claim 1, wherein the compound is selected from the group consisting of:


28. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated for oral administration.
 29. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is formulated in a liquid dosage form.
 30. The compound of claim 5, wherein the compound is


31. The compound of claim 5, wherein the compound is


32. The method of claim 9, wherein the administration is via oral, nasal, intravenous, subcutaneous, or intramuscular administration. 